4-Substituted-2-oxoazetidine compounds

ABSTRACT

The present invention relates to novel 4-substituted-2-oxoazetidine compounds and to processes for preparing the same. These compounds are useful intermediates for preparing antibiotics having the basic skeleton of Thienamycin.

This application is continuation-in-part of application Ser. No. 237,936filed Feb. 25, 1981, now abandoned and a continuation-in-part ofapplication Ser. No. 296,840 filed Aug. 27, 1981, now U.S. Pat. No.4,383,945.

The present invention relates to novel 4-substituted-2-oxoazetidinecompounds and salts thereof. More particularly, it relates to novel4-substituted-2-oxoazetidine compounds and salts thereof, which areuseful intermediates for preparing antibiotics having the fundamentalskeleton of Thienamycin and to processes for the preparation thereof.

Accordingly, one object of the present invention is to provide novel4-substituted-2-oxoazetidine compounds and salts thereof, which areuseful intermediates for preparing antibiotics having the fundamentalskeleton of Thienamycin, which are highly active against a number ofpathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of 4-substituted-2-oxoazetidine compounds and salts thereof.

The object 4-substituted-2-oxoazetidine compounds can be represented bythe following general formula: ##STR1## or a salt thereof, in which

R¹ is hydrogen, halogen, amino, acylamino, isocyano lower alkyl,hydroxy(lower)alkyl, or protected hydroxy(lower)-alkyl,

R² is hydrogen or an organic group optionally substituted by suitablesubstituent(s), and

R³ is carboxy or a protected carboxy group.

In the object compounds and the starting compounds in Processes A to Qmentioned below, it is to be understood that there may be one or morestereoisomeric pair(s) such as optical and/or geometrical isomers due toasymmetric carbon atom(s) and double bond(s) in those molecules, andthese isomers are also included within the scope of the presentinvention.

Suitable salts of the object compounds (I) are conventional basic oracidic salts and may include an inorganic basic salt, for example, ametal salt such as an alkali metal salt (e.g. sodium salt, potassiumsalt, etc.) and an alkaline earth metal salt (e.g. calcium salt,magnesium salt, etc.), and an ammonium salt etc.; an organic basic salt,for example, an organic amine salt [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, N-methylglucamine salt,diethanolamine salt, triethanolamine salt,tris(hydroxymethylamino)methane salt, etc.] etc.; an organic carboxylicor sulfonic acid addition salt (e.g. formate, acetate, maleate,tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.);an inorganic acid addition salt (e.g. hydrochloride, hydrobromide,sulfate, phosphate, etc.); a salt with a basic or acidic amino acid(e.g. arginine, aspartic acid, glutamic acid, etc.), and the like.

According to the present invention, the object compounds and saltsthereof (I) can be prepared by the processes as illustrated by thefollowing reaction schemes. ##STR2## in which R² and R³ are each asdefined above,

R_(a) ¹ is hydrogen, halogen, amino, a protected amino group, isocyano,lower alkyl, hydroxy(lower)alkyl or a protected hydroxy(lower)alkyl,

R_(b) ¹ is a protected amino group,

R_(c) ¹ and R^(a) are each halogen, R_(d) ¹ is a protectedhydroxy(lower)alkyl, R_(e) ¹ is hydroxy(lower)alkyl, R_(f) ¹ is loweralkyl or hydroxy(lower)alkyl, R_(g) ¹ is hydroxy(lower)alkyl or aprotected hydroxy(lower)alkyl, R_(h) ¹ is 1-hydroxy-1-methylethyl or1-protected hydroxy-1-methylethyl, R⁵ is aryl, lower alkyl or loweralkoxy, R^(b) is carboxy or a protected carboxy group, R^(c) is loweralkyl, Z is a group of the formula:

    --Si(R.sup.4).sub.3 or --Sn(R.sup.4).sub.3

wherein

R⁴ is lower alkyl, aryl, lower alkoxy or halogen,

R⁶ and R⁷ are each lower alkyl; or R⁶ and R⁷ are linked together to formcycloalkylidene.

R⁸ is carboxy or a protected carboxy, R⁹ is acyl,

R¹⁰ is acylamino(lower)alkyl or acylamino(lower)alkenyl, and R_(a) ¹⁰ isamino(lower)alkyl, acylamino(lower)alkyl or acylamino(lower)alkenyl.

Some of the starting compounds (II) and (III) in Process A are novel andcan be prepared, for example, from the known compounds by the method inthe following reaction schemes or a conventional method thereof.##STR3## in which R_(a) ¹, R_(d) ¹, R³, R^(a) and Z are each as definedabove,

R_(e) ¹ is hydroxy(lower)alkyl,

R_(a) ² is carboxy(lower)alkyl,

R_(b) ² is protected carboxy(lower)alkyl, and

R^(d) is lower alkyl.

In the above and subsequent description of the present specification,suitable examples and illustration of the various definitions to beincluded within the scope thereof are explained in detail as follows.

The term "lower" in the present specification is intended to mean agroup having 1 to 6 carbon atom(s), and the term "higher" is intended tomean a group having 7 to 20 carbon atoms, unless otherwise indicated.

Suitable "halogen" may include chlorine, bromine and iodine.

Suitable "a protected amino group" may include an amino groupsubstituted with a suitable protective group which is conventionallyused in cephalosporin and penicillin compounds as a protective group ofthe amino group at their 7th or 6th position, and a suitable "aprotected amino group" may include acylamino, mono- or di- ortri-phenyl(lower)alkylamino (e.g. benzylamino, benzhydrylamino,tritylamino, etc.), a group of the formula: ##STR4## and the like.

Suitable "acyl moiety" in the term "acylamino" may include aliphaticacyl group and acyl group containing an aromatic ring, which is referredto as aromatic acyl, or heterocyclic ring, which is referred to asheterocyclic acyl.

Suitable example of said acyl may be illustrated as follows:

Aliphatic acyl such as lower or higher alkanoyl (e.g. formyl, acetyl,succinyl, hexanoyl, heptanoyl, stearoyl, etc.);

lower or higher alkenoyl (e.g. acryloyl, maleoyl, etc.);

lower or higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl,t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.);

lower or higher alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl,etc.); or the like;

Aromatic acyl such as

aroyl (e.g. benzoyl, toluoyl, naphthoyl, phthaloyl, etc.)ar(lower)alkanoyl such as phenyl(lower)alkanoyl (e.g. phenylacetyl,phenylpropionyl, etc.);

aryloxycarbonyl (e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.);

aryloxy(lower)alkanoyl such as phenoxy(lower)alkanoyl (e.g.phenoxyacetyl, phenoxypropionyl, etc.);

arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.);

arenesulfonyl (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.); or thelike;

Heterocyclic acyl such as

heterocycliccarbonyl (e.g. thenoyl, furoyl, nicotinoyl, etc.);

heterocyclic(lower)alkanoyl (e.g. thienylacetyl, thiazolylacetyl,tetrazolylacetyl, etc.);

heterocyclicglyoxyloyl (e.g. thiazolylglyoxyloyl, thienylglyoxyloyl,etc.); or the like; in which suitable heterocyclic moiety in the terms"heterocycliccarbonyl", "heterocyclic(lower)alkanoyl" and"heterocyclicglyoxyloyl" as mentioned above means, in more detail,saturated or unsaturated, monocyclic or polycyclic heterocyclic groupcontaining at least one hetero-atom such as an oxygen, sulfur, nitrogenatom and the like.

And, especially preferable heterocyclic group may be heterocyclic groupsuch as

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide,dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (e.g.4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.),tetrazolyl (e.g. 1H-tetrazolyl, 2H-tetrazolyl, etc.) etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example,pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; unsaturatedcondensed heterocyclic group containing 1 to 4 nitrogen atom(s), forexample, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl,isoquinolyl, indazolyl, benzotriazolyl, etc.; unsaturated 3 to8-membered (more preferably 5 or 6-membered) heteromonocyclic groupcontaining 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), forexample, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, morpholinyl, sydnonyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl,benzoxadiazolyl, etc.; unsaturated 3 to 8 membered (more preferably 5 or6-membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;

saturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3nitrogen atom(s), for example, thiazolidinyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing 1 to 2 sulfur atom(s), for example,thienyl, dihydrodithiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl,benzothiadiazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5or 6-membered) heteromonocyclic group containing an oxygen atom, forexample, furyl, etc.;

unsaturated 3 to 8-membered (more preferably 5 or 6-membered)heteromonocyclic group containing an oxygen atom and 1 to 2 sulfuratom(s), for example, dihydrooxathiinyl, etc.;

unsaturated condensed heterocyclic group containing 1 to 2 sulfuratom(s), for example, benzothienyl, benzodithiinyl, etc.;

unsaturated condensed heterocyclic group containing an oxygen atom and 1to 2 sulfur atom(s), for example, benzoxathiinyl, etc. and the like.

The acyl moiety thus defined may optionally be substituted by one toten, same or different, suitable substituent(s) such as:

lower alkyl (e.g. methyl, ethyl, etc.);

lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.);

lower alkylthio (e.g. methylthio, ethylthio, etc.);

lower alkylamino (e.g. methylamino, etc.); cyclo(lower)alkyl (e.g.cyclopentyl, cyclohexyl, etc.); cyclo(lower)alkenyl (e.g. cyclohexenyl;cyclohexadienyl, etc.); hydroxy; halogen (e.g. chloro, bromo, etc.);amino; protected amino as aforementioned; cyano; nitro; carboxy;protected carboxy as mentioned below; sulfo; sulfamoyl; imino; oxo;amino(lower)alkyl (e.g. aminomethyl, aminoethyl, etc.).

The preferred embodiment of "acylamino" thus defined may includearoylamino such as phthalimido.

Suitable "protected hydroxy(lower)alkyl" means lower alkyl substitutedby a conventional protected hydroxy group and may includeacyloxy(lower)alkyl, in which the acyl moiety may include the same asthose exemplified above and the lower alkyl moiety may include methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,neopentyl, tert-pentyl, hexyl and the like, and the preferred embodimentof "protected hydroxy(lower)alkyl" thus defined may include substitutedor unsubstituted ar(lower)alkoxycarbonyloxy(lower)alkyl such as mono- ordi- or tri-phenyl(lower)alkoxycarbonyloxy(lower)alkyl optionallysubstituted by nitro (e.g. benzyloxycarbonyloxymethyl,benzhydryloxycarbonyloxymethyl, trityloxycarbonyloxymethyl, 1- or2-benzyloxycarbonyloxyethyl, 1- or 2-benzhydryloxycarbonyloxyethyl,p-nitrobenzyloxycarbonyloxymethyl, 1- or2-p-nitrobenzyloxycarbonyloxyethyl, 1- or 2- or3-p-nitrobenzyloxycarbonyloxypropyl, etc.).

Suitable "hydroxy(lower)alkyl" may include hydroxymethyl, 1- or2-hydroxyethyl, 1- or 2- or 3-hydroxypropyl, and the like.

Suitable "a protected carboxy group" may include a carboxy groupsubstituted with a suitable protective group which is conventionallyused in cephalosporin and penicillin compounds as the protective groupof the carboxy group at their 4th or 3rd position, for example, anesterified carboxy group. And suitable examples of said ester moiety maybe the ones such as lower alkyl ester (e.g. methyl ester, ethyl ester,propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butylester, pentyl ester, tert-pentyl ester, hexyl ester, etc.);

lower cycloalkyl(lower)alkyl ester (e.g. 1-cyclopropylethyl ester,etc.);

lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.);

lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.);

lower alkoxyalkyl ester (e.g. methoxymethyl ester, ethoxymethyl ester,isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester,etc.);

lower alkylthioalkyl ester (e.g. methylthiomethyl ester, ethylthiomethylester, ethylthioethyl ester, isopropylthiomethyl ester, etc.);

mono (or di or tri)-halo(lower)alkyl ester (e.g. 2-iodoethyl ester,2,2,2-trichloroethyl ester, etc.);

lower alkanoyloxy(lower)alkyl ester (e.g. acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethylester, 2-propionyloxyethyl ester, etc.);

lower alkanesulfonyl(lower)alkyl ester (e.g. mesylmethyl ester,2-mesylethyl ester, etc.);

ar(lower)alkyl ester, for example, phenyl(lower)alkyl ester optionallysubstituted by one or more suitable substituent(s) such as nitro,hydroxy, lower alkoxy or the like [e.g. benzyl ester, 4-methoxybenzylester, 4-nitrobenzyl ester, phenethyl ester, trityl ester,diphenylmethyl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.];

aryl ester optionally substituted by one or more suitable substituent(s)such as substituted or unsubstituted phenyl ester optionally substitutedby halogen, lower alkoxy or the like (e.g. phenyl ester, tolyl ester,t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester,4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri(lower)alkylsilyl ester (e.g. trimethylsilyl ester, etc.);

lower alkylthioester (e.g. methylthioester, ethylthioester, etc.) andthe like, in which the preferred "esterified carboxy group" may includelower alkoxycarbonyl (e.g methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, tert-pentyloxycarbonyl,hexyloxycarbonyl, etc.) and mono- or di- ortriphenyl(lower)alkoxycarbonyl optionally substituted by nitro (e.g.benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl,4-nitrobenzyloxycarbonyl, etc.).

Suitable "an organic group optionally substituted by suitablesubstituent(s)" may include lower alkyl (e.g. methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, hexyl, etc.),aryl (e.g. phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl, etc.),these groups substituted by one or more suitable substituent(s) such ascarboxy, a protected carboxy group mentioned above, lower alkylthio(e.g. methylthio, ethylthio, propylthio, etc.), and the like.

The preferred embodiment of "an organic group substituted by suitablesubstitutent(s)" may include carboxy(lower)alkyl (e.g. carboxymethyl, 1-or 2-carboxyethyl, 1- or 2- or 3-carboxypropyl, etc.), and protectedcarboxy(lower)alkyl such as lower alkoxycarbonyl(lower)alkyl (e.g.methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, 1-or 2-methoxycarbonylethyl, 1- or 2-ethoxycarbonylethyl, etc.), and mono-or di- or tri-phenyl(lower)alkoxycarbonyl(lower)alkyl optionallysubstituted by nitro (e.g. benzyloxycarbonylmethyl,benzyloxycarbonylethyl, benzyloxycarbonylpropyl,benzhydryloxycarbonylmethyl, trityloxycarbonylmethyl,p-nitrobenzyloxycarbonylmethyl, p-nitrobenzyloxycarbonylethyl,p,p'-dinitrobenzhydryloxycarbonylpropyl, etc.).

Suitable "carboxy(lower)alkyl" and "protected carboxy(lower)alkyl" mayinclude the same as those exemplified above, respectively.

Suitable "lower alkyl" may include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, andthe like, in which the preferred one may include C₁ -C₃ alkyl.

Suitable "cycloalkylidene" may include 5-6 membered cycloalkylidene (i.ecyclopentylidene and cyclohexylidene, etc.).

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and thelike, in which the preferred one may include C₁ -C₃ alkoxy.

Suitable "aryl" may include phenyl, tolyl, xylyl, mesityl, cumenyl,naphthyl, and the like.

Suitable "protected hydroxy moiety" in the terms "1-protectedhydroxy-1-methylethyl" and "protected hydroxy(lower)alkyl" may include ahydroxy group substituted by a conventional hydroxy-protective group,which is commonly used in β-lactam compounds such as thienamycin orcarpetimycin derivatives or its analogue, for example, acyl such asmono(or di or tri)phenyl(lower)alkoxycarbonyl optionally substituted bynitro (e.g. benzyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl,4-nitrobenzyloxycarbonyl, etc.), ar(lower)alkyl such as mono(or di- ortri)phenyl(lower)alkyl (e.g. benzyl, benzhydryl, trityl, etc.),trisubstituted silyl such as tri(lower)alkylsilyl (e.g. trimethylsilyl,triethylsilyl, isopropyl-dimethylsilyl, tert-butyldimethylsilyl,diisopropyl-methylsilyl, etc.), triarylsilyl (e.g. triphenylsilyl, etc.)or triar(lower)alkylsilyl (e.g. tribenzylsilyl, etc.), and the like.

Suitable "lower alkyl moiety" in the terms "amino(lower)alkyl" and"acylamino(lower)alkyl" may include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, andthe like, in which the preferred one may include C₁ -C₃ alkyl.

Suitable "lower alkenyl moiety" in the term "acylamino(lower)alkenyl"may include vinyl, propenyl and the like.

Suitable "acyl moiety" in the terms "acylamino(lower)alkyl" and"acylamino(lower)alkenyl" may include lower alkanoyl (e.g. formyl,acetyl, etc.), phenyl(lower)alkoxycarbonyl which may have nitro (e.g.benxyloxycarbonyl, 4-nitrobenxyloxycarbonyl, ect.), and the like.

Suitable "acyl" may include a residue of an organic sulfonic orphosphoric acid such as diaryloxyphosphoryl (e.g. diphenoxyphosphoryletc.). Suitable salts of the compound (I'), (I-2), (II), (II-I) to(II-3), (VII-4), (VIII-3), (XVIII) and (XXIII) to (XXV) are the same asthose exemplified for the compound (I).

Suitable salts of the compounds (I-1), (I-3) to (I-10), (I-11), (I-12),(I-4a), (II-4), (II-5), (III), (III-1), (IV-1) to (IV-3), (V-1), (V-3)to (V-6), (VI), (VII-1) to (VII-3), (VII-5) to (VII-7), (VIII-2),(IX-1), (IX-2), (XXII), and (XXVI) to (XXX) are the same as the basicsalts as exemplified for the compound (I).

Suitable acetal at the formyl group of the compounds (V-1), (V-2),(VIII-1) and (X) may include di(lower)alkyl acetal such asdi(lower)alkoxymethyl (e.g. dimethoxymethyl, diethoxymethyl,dipropoxymethyl, etc.), and the like.

Suitable hemi-acetal at the formyl group of the compound (VIII-1) mayinclude lower alkyl hemi-acetal such as 1-hydroxy-1-(lower)alkoxymethyl(e.g. 1-hydroxy-1-methoxymethyl, 1-hydroxy-1-ethoxymethyl,1-hydroxy-1-propoxymethyl, etc.), and the like.

The processes for the preparation of the object compounds of the presentinvention are explained in detail in the following.

Process A: (II)→(I')

The object compound (I') can be prepared by reacting the compound (II)with the compound (III).

This reaction is preferably carried out in the presence of adehalogenating agent such as silver compounds (e.g. silvertetrafluoroborate, silver perchlorate, etc.), Lewis acids (e.g. titaniumtetrachloride, zinc chloride, mercuric chloride, boron trifluorideetherate, etc.), and the like.

Further, this reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction such as chloroform,methylene chloride, tetrahydrofuran, benzene, etc., or a mixturethereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under warming.

This reaction proceeds stereospecifically, and the configuration of thethird and fourth positions of the object compound (I') alwaysconstitutes a trans form. Accordingly, the compound (I'), for example,having the same configuration as that of the natural Thienamycin can beprepared depending on a selection of the starting compound (II).

Process B-1: (I-1)→(I-2),

Process E-4: (VII-3)→(VII-4),

Process F-4: (VIII-2)→(VIII-3) and

Process M-3: (XVII)→(XVIII)

The object compounds (I-2), (VII-4), (VIII-3) and (XVIII) can beprepared by removing the amino-protective group in R_(b) ¹ from thecorresponding compounds (I-1), (VII-3), (VIII-2) and (XVIII),respectively.

Suitable method for this removal reaction includes hydrolysis;reduction; a combined method comprising iminohalogenation andiminoetherification, followed by hydrolysis; and the like.

In the above methods, suitable reagents to be used are exemplified asfollows.

(i) For hydrolysis which refers to the same meaning as solvolysisincluding, for example, acidolysis, alcoholysis, aminolysis,hydrazinolysis, etc.:

Hydrolysis is preferably carried out in the presence of an acid or base.

Suitable acid is an inorganic acid (e.g. hydrochloric acid, hydrobromicacid, sulfuric acid, etc.), an organic acid (e.g. formic acid, aceticacid, trifluoroacetic acid, propionic acid, benzenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid, etc.), an acidicion-exchange resin and the like.

Suitable base is an inorganic base such as alkali or alkaline earthmetal hydroxide, carbonate or bicarbonate (e.g. sodium hydroxide,potassium carbonate, sodium bicarbonate, calcium hydroxide, magnesiumhydroxide, etc.), ammonium hydroxide and the like; an organic base suchas an alkoxide or phenoxide of the above metal, (e.g. sodium ethoxide,sodium methoxide, lithium phenoxide), an amine such as mono-, di- ortrialkylamine (e.g. methylamine, ethylamine, propylamine,isopropylamine, butylamine, N,N-dimethyl-1, 3-propanediamine,trimethylamine, triethylamine, etc.), unsubstituted, mono- ordisubstituted arylamine (e.g. aniline, N-methylanilineN,N-dimethylaniline, etc.) or a heterocyclic base (e.g. pyrrolidine,morpholine, N-methylmorpholine, N-methylpiperidine,N,N-dimethylpiperazine, pyridine, etc.), hydrazines (e.g. hydrazine,methylhydrazine, ethylhydrazine, etc.), a basic ion exchange resin andthe like.

The hydrolysis is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, tetrahydrofuran, N,N-dimethylformamide, dioxane,methylene chloride, chloroform, etc., or a mixture thereof.

The reaction temperature of this hydrolysis is not critical and thereaction is preferably carried out from under cooling to under warming.

(ii) For reduction:

Reduction is carried out in a conventional manner, including chemicalreduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of a metal (e.g. tin, zinc, iron, etc.) or a metalliccompound (e.g. chromium chloride, chromium acetate, etc.) and an organicor inorganic acid (e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.).

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, lower alkanol(e.g. methanol, ethanol, propanol, etc.), chloroform, methylenechloride, tetrahydrofuran, N,N-dimethylformamide, benzene, toluene,etc., or a mixture thereof. Additionally, in case that theabovementioned acids to be used in chemical reduction are in liquid,they can also be used as a solvent.

The reaction temperature of this reduction is not critical and thereaction is preferably carried out from under cooling to under warming.

(iii) For combined method:

In this process, when the protected amino group in R_(b) ¹ is an organiccarboxamide, the carboxamide bond can be more preferably cleaved by thefollowing modified hydrolysis. That is, the compounds (I-1), (VII-3) and(VIII-2) are first subjected to iminohalogenation, iminoetherification,and then hydrolysis.

The first and second steps of this method are preferably carried out inan anhydrous solvent. Suitable solvent for the first step (i.e.iminohalogenation) is an aprotic solvent such as methylene chloride,chloroform, diethyl ether, tetrahydrofuran, dioxane, etc., and for thesecond step (i.e. iminoetherification) is usually the same as those inthe above first step. These two steps and the last step (i.e. hydrolysisstep) are most preferably conducted in one-batch system.

Suitable iminohalogenating agent includes a halogenating agent such asphosphorus compound (e.g. phosphorus trichloride, phosphoruspentachloride, phosphorus tribromide, phosphorus pentabromide,phosphorus oxychloride, etc.), thionyl chloride, phosgene, and the like.

Suitable iminoetherifying agent may be an alcohol such as an alkanol(e.g. methanol, ethanol, propanol, isopropanol, butanol, etc.) or thecorresponding alkanol having alkoxy (e.g. 2-methoxyethanol,2-ethoxyethanol, etc.), and alkoxide of metal such as alkali metal,alkaline earth metal (e.g. sodium methoxide, potassium ethoxide,magnesium ethoxide, lithium methoxide, etc.), and the like. Thusobtained reaction product is, if necessary, hydrolyzed in a conventionalmanner.

The hydrolysis is preferably carried out at ambient temperature or undercooling, and proceeds simply pouring the reaction mixture into water ora hydrophilic solvent such as alcohol (e.g. methanol, ethanol, etc.)moistened or admixed with water, and if necessary, with addition of anacid or base as exemplified in the hydrolysis.

The method for this removal reaction is selected according to a kind ofthe amino-protective group to be removed.

In addition to the above, in case the protected amino group in R_(b) ¹is a group such as phthalimido, the reaction can also be carried out byreacting the compounds (I-1), (VII-3) and (VIII-2) with a dimetalsulfide (e.g. disodium sulfide, etc.), and then a condensing agent (e.g.N,N'-dicyclohexylcarbodiimide, ethyl chloroformate-triethylamine,trifluoroacetic anhydride, etc.), followed by hydrazine. The presentremoval reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction as aforementioned from undercooling to under warming.

In this reaction, the starting compounds (I-1), (VII-3) and (VIII-2) canbe used as a protected form at the first position thereof, and suchprotected form may be, for example, a silyl derivative formed by thereaction of the starting compounds with a silyl compound such astetra(lower)alkylsilane (e.g. tert-butyltrimethylsilane, etc.), and thelike.

Process B-2: (I-2)→(I-3)

The object compound (I-3) can be prepared by reacting the compound (I-2)with a diazotizing agent and a halogenating agent.

The diazotizing agent used in this reaction may include a conventionalone which can be applied to converting amino compounds to diazocompounds such as alkali metal nitrite (e.g. sodium nitrite, etc.),alkyl nitrite (e.g. pentyl nitrite, isopentyl nitrite, etc.), nitrosylchloride, dinitrogen tetroxide, and the like.

The halogenating agent used in this reaction may include a conventionalone which can be applied to converting diazo compounds to halo compoundssuch as hydrogen halide (e.g. hydrogen chloride, hydrogen bromide,etc.), hydrogen halide with an organic amine, for example, hydrogenhalide with trialkylamine (e.g. triethylamine hydrochloride,triethylamine hydrobromide, etc.), and the like.

When hydrogen halide with an organic amine is used as the halogenatingagent, the reaction can preferably be carried out in the presence of anacid as those illustrated in Process B-1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, formic acid,acetic acid, tetrahydrofuran, chloroform, methylene chloride, benzene,etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under warming.

Process B-3: (I-3)→(I-4)

The object compound (I-4) can be prepared by removing halogen for R_(c)¹ from the compound (I-3).

This reaction is carried out by a conventional method such as reductionand the like.

The method of reduction, and the reaction conditions (e.g. reactiontemperature, solvent, etc.) are substantially the same as thoseillustrated for the removal reaction of the amino-protective group inR_(b) ¹ of the compound (I-1) in the Process B-1, and therefore are tobe referred to said explanation, and in addition, there may beexemplified by trialkyltin hydride [e.g. tri(n-butyl)tin hydride, etc.]triaryltin hydride (e.g. triphenyltin hydride, etc.) as the reducingagent.

Process B-4: (I-2)→(I-5)

Process E-5: (VII-4)→(VII-5) and

Process M-4: (XVIII)→(XIX)

The object compounds (I-5), (VII-5) and (XVIII) can be prepared byformylating the corresponding compounds (I-2), (VII-4) and (XIX),respectively.

The formylating agent used in this reaction may include formic acid orits salt or its reactive derivative such as formic acid anhydride (e.g.formic anhydride, formic acetic anhydride, etc.), formylimidazole, andthe like.

In this reaction, in case that a free formic acid is used as theformylating agent, the reaction is preferably carried out in thepresence of a condencing agent such as a carbodiimide compound [e.g.,N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide,N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, etc.], a keteniminecompound (e.g., N,N'-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine, etc.); an olefinic or acetylenic ethercompounds (e.g., ethoxyacetylene, β-chlorovinylethyl ether), a sulfonicacid ester of N-hydroxybenzotriazole derivative [e.g.,1-(4-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, etc.], acombination of trialkylphosphite or triphenylphosphine and carbontetrachloride, disulfide or diazacarboxylate, a phosphorus compound(e.g., ethyl polyphosphate, isopropyl polyphosphate, phosphorylchloride, phosphorus trichloride, etc.), thionyl chloride, oxalylchloride, N-ethylbenzisoxazolium salt,N-ethyl-5-phenylisoxazolium-3-sulfonate, a reagent (referred to asso-called "Vilsmeier reagent") formed by the reaction of an amidecompound such as dimethylformamide, diethylacetamide, N-methylformamide,etc.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran, dioxane, formic acid,acetic acid, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under warming.

Process B-5: (I-5)→(I-6)

Process E-6: (VII-5)→(VII-6) and

Process M-5: (XIX)→(XX)

The object compounds (I-6), (VII-6) and (XX) can be prepared bydehydrating the corresponding compounds (I-5), (VII-5) and (XIX),respectively.

The dehydrating agent used in this reaction may include conventional onesuch as phosphorus halocompound (e.g. phosphorus trichloride, phosphorustribromide, phosphorus oxychloride, phosphorus pentachloride, etc.),triphenylphosphine dibromide, phosphorus pentoxide, phosgene, thionylchloride, trichloromethyl chloroformate, isocyanuric chloride, sulfonylhalide (e.g. benzenesulfonyl chloride, toluenesulfonyl chloride etc.)and the like.

This reaction is preferably carried out in the presence of a base asaforementioned in Process B-1.

Further, this reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran, dioxane and thelike.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to at ambient temperature.

Process B-6: (I-6)→(I-4)

Process E-7: (VII-6)→(VII-7)

Process I-2: (XI)→(I-11)

Process J-2: (XIII)→(XIV) and

Process M-6: (XX)→(XXI)

The object compounds (I-4), (VII-7), (I-11), (XIV) and (XXI) can beprepared by removing the isocyano group from the corresponding compounds(I-6), (VII-6), (XI), (XIII) and (XX), respectively.

This removal reaction can be carried out in the presence of a reducingagent, and suitable example thereof may include tri- or dialkyltinhydride and tri- or diaryltin hydride as exemplified in Process B-3.

In this process, when a compound (XI) or (XIII) wherein R_(e) ¹ is aprotected hydroxy(lower)alkyl is used as a starting compound, thecorresponding compound (I-11) or (XIV) wherein R_(e) ¹ is a protectedhydrocy(lower)alkyl can be obtained as a resultant compound. This casemay also be included within the scope of this process.

Process C-1: (I-4a)→(IV-1),

Process D-4: (V-3)→(V-4) and

Process F-3: (VIII-2)→(VII-2)

The object compounds (IV-1), (V-4) and (VII-2) can be prepared byoxidizing the corresponding compounds (I-4a), (V-3) and (VIII-2),respectively.

The oxidizing agent used in this reaction may include a conventional onewhich can be applied to converting an allyl group to an acetyl groupsuch as oxygen, hydrogen peroxide, lower alkyl hydrogen peroxide (e.g.tert-butyl hydrogen peroxide, etc.) in the presence of palladiumcompound (e.g. palladium chloride, sodium tetrachloropalladate, etc.)optionally in the presence of cupric halide (eg. cupric chloride, etc.)or cuprous halide (e.g. cuprous chloride, etc.), and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influince the reaction such as water, methanol,ethanol, isopropyl alcohol, N,N-dimethylformamide, N-methylpyrrolidone,acetic acid, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under heating.

In this reaction, the starting compounds (I-4a) and (VIII-2) can be usedas a protected form at the first position thereof, and such protectedform may be, for example, a silyl derivative formed by the reaction ofthe starting compounds with a silyl compound such as tetraalkylsilane(e.g. tert-butyl-trimethylsilane, etc.), and the like.

Process C-2: (IV-1)→(IV-2),

Process D-1: (I-4a)→(V-1),

Process E-1: (I-7)→(VII-1) and

Process G-1: (I-9)→(IX-1)

The object compounds (IV-2), (V-1), (VII-1) and (IX-1) can be preparedby reacting the corresponding compounds (IV-1), (I-4a), (I-7) and (I-9),respectively with ozone, and then degrading the resultant ozonide in aconventional manner, if necessary.

The ozonide produced by the starting compounds with ozone is usuallydegraded by redution or heating.

The method of the reduction can be carried out in substantially the samemanner as that as explained in Process B-1, and therefore the reactionconditions (e.g. solvent, reaction temperature, etc.) are to be referredto said explanation, and in addition, as suitable reducing agents, theremay be exemplified by trialkyl phosphite (e.g. trimethylphosphite,etc.), triphenylphosphine, dimethyl sulfide, sodium bisulfite, sodiumsulfite, sodium iodide, stannous chloride, and the like.

In this reaction, in case that lower alkanol is used as the solvent, theacetal or hemi-acetal of the object compounds (V-1) and (IX-1) areoccasionally obtained, and this is also included within the scope ofthis reaction.

Further, in case that the compound (I-4a) is used as the startingcompound, and the degradation reaction is carried out by heating, thecompound (XI-1) represented by the following formula is also obtained.

In case that the reaction is carried out by heating, the compound (XI-1)can also be prepared, from the ozonide, and this compound can betransformed into the comoound (XI-2) by Hydrolysis in Process D-2 andintroduction of the carboxyprotective group in a conventional manner asexplained in Preparation E mentioned hereinafter. ##STR5## wherein R³ isa protected carboxy such as those exemplified above. Process C-3:(IV-2)→(IV-3)

Process D-5: (V-2)→(V-5)

Process D-6: (V-1)→(V-6) and

Process M-1: (VIII-1)→(XVI)

The object compounds (IV-3), (V-5), (V-6) and (XVI) can be prepared byreducing the corresponding compounds (IV-2), (V-2), (V-1) and (VIII-1),respectively.

The reducing agent to be used in this reaction may include conventionalreducing agent which can reduce an oxo group to a hydroxy group such asthose exemplified in Process B-1, and in addition, alkali metalborohydride (e.g. sodium borohydride, sodium cyanoborohydride, etc.),borane complex with amines (e.g. tert-butylamine, N,N-dimethylaniline,lutidine, morpholine, triethylamine, etc.), borane complex with ethers(e.g. tetrahydrofuran, etc.), diborane, alminum-amalgam and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methylenechloride, methanol ethanol, ethyl acetate, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out from under cooling to under warming.

Process D-2: (V-1)→(V-2),

Process E-2: (VII-1)→(VII-2) and

Process G-2: (IX-1)→(IX-2)

The object compounds (V-2), (VII-2) and (IX-2) can be prepared byhydrolyzing the corresponding compounds (V-1), (VII-1) and (IX-1),respectively.

This reaction can be carried out in substantially the same manner asHydrolysis as explained in Process B-1, and therefore the reactionconditions (e.g. solvent, reaction temperature, etc.) are to be referredto said explanation.

This reaction is preferably carried out by alcoholysis such asmethanolysis.

In this reaction, in case that the object compound (V-2) is obtained asthe acetal, it can be transformed into the compound (V-2) having theformyl group in a conventional manner, for example, by treating theacetal with acids as exemplified in Process B-1.

Process D-3: (V-2)→(V-3) and

Process F-2: (VIII-1)→(VIII-2)

The object compounds (V-3) and (VIII-2) can be prepared by reacting thecorresponding compounds (V-2) and (VIII-1) with the compound (VI).

The reactive equivalent of the compound (VI) can also be used in thisreaction, and such reactive equivalent can be represented by the formula(R⁵ O)₂ POCH₂ R^(b), in which R⁵ and R^(b) are each as defined above.

In case that the above reactive equivalent is used in this reaction, thereaction is preferably carried out in the presence of a base asexemplified in Process B-1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran, dioxane, etc., or amixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under heating.

In this reaction, the starting compounds (V-2) and (VIII-1) can be usedas a protected form at the first position thereof, and such protectedform may be, for example, a silyl derivative formed by the reaction ofthe starting compounds with a silyl compound such as tetraalkylsilane(e.g. tert-butyl-trimethylsilane, etc.), and the like.

Process F-1: (I-8)→(VIII-1) and

Process H: (I-10)→(X)

The object compounds (VIII-1) and (X) can be prepared by reacting thecorresponding compounds (I-8) and (I-10) with ozone, and degrading theresultant ozonide in a conventional manner, if necessary, and thenhydrolyzing the resultant compound in a conventional manner.

This reaction can be carried out by substantially the same method asthose of Processes C-2 and D-2, and therefore the reaction conditions(e.g. solvent, reaction temperature, etc,) are to be referred to saidexplanation.

In this reaction, in case that the object compound (VIII-1) is obtainedas the acetal form, it can be transformed into the compound (VIII-1)having the formyl group in a conventional manner, for example, bytreating the acetal with acids as exemplified in Process B-1.

Process E-3: (VII-2)→(VII-3)

The object compound (VII-3) can be prepared by subjecting the compound(VII-2) to protection reaction of the carbonyl group.

The reagent used in this reaction may include tri(lower)alkylorthoformate (e.g. trimethyl orthoformate, etc.), O,O-di(lower)alkylketone (e.g. O,O-dimethyl acetone, etc.), lower alkanol (e.g. methanol,etc.), and the like.

This reaction is preferably carried out in the presence of an acid suchas those exemplified in Hydrolysis in Process B-1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as methylene chloride,chloroform, benzene, toluene, tetrahydrofuran, dioxane, etc., or amixture thereof.

The reaction temperature of this reaction is not critical and thereaction is preferably carried out from under cooling to under heating.

Process E-8: (VII-7)→(V-4)

The object compound (V-4) can be prepared by removing thecarbonyl-protective group in the protected carbonyl group from thecompound (VII-7).

This reaction can be carried out in the presence of an acid such asthose exemplified in Hydrolysis in Process B-1.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water,dimethylformamide, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to under heating.

Process I-1: (I-6)→(XI)

Process J-1: (XII)→(XIII)

The object compounds (XI) and (XIII) can be prepared by reacting thecorresponding compounds (I-6) and (XII) with an organo lithium compound,respectively and then reacting the resultant compound with a carbonylcompound.

The organo lithium compound may include alkyl lithium (e.g. n-butyllithium, etc.), aryl lithium, aralkyl lithium and the like.

The carbonyl compound to be used in this reaction may includeoxo(lower)alkane (e.g. acetone, acetaldehyde, etc.) and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,dimethoxyethane, ether and the like.

The reaction temperature of this reaction is not critical and thereaction is preferably carried out from under cooling to at ambienttemperature.

Process J-3: (XIV)→(XV)

Process L: (I-11)→(I-13)

Process N: (I-2a)→(I-8)

The object compounds (XV), (I-13) and (I-8) can be prepared bysubjecting the corresponding compounds (XIV), (I-11) and (I-2a) tointroduction reaction of the hydroxy-protective group or theamino-protective group, respectively.

This reaction is substantially the same as Preparation C as mentionedhereinafter, and further, the introducing agent of the amino-protectivegroup is substantially the same as those of hydroxy-protective group.

Therefore the introducing agent of the hydroxy-protective group (or theamino-protective group) and reaction conditions (e.g. reactiontemperature, solvent, etc.) are referred to those of the Preparation C.

Process K: (I-4a)→(I-12)

The object compound (I-12) can be prepared by reacting the compound(I-4a) with a metal amide and then reacting the resultant compound witha carbonyl compound or alkyl halide.

The metal amide to be used in this reaction may include an alkali metalamide (e.g. lithium isopropyl cyclohexylamide, etc.) and the like.

The carbonyl compound to be used in this reaction may includeoxo(lower)alkane (e.g. acetone, acetaldehyde, etc.) and the like.

The alkyl halide to be used in this reaction may include methyl iodide,ethyl iodide and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as tetrahydrofuran,dimethoxyethane, ether and the like.

The reaction temperature of this reaction is not critical and thereaction is preferably carried out from under cooling to at ambienttemperature.

Process M-2: (XVI)→(XVII)

The object compound (XVII) can be prepared by reacting the compound(XVI) with 2,2-dimethoxyalkane (e.g. 2,2-dimethoxypropane, etc.) ordimethoxycycloalkane in the presence of a Lewis acid.

The Lewis acid may include a conventional one such as boron trifluorideetherate and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as dichloromethane,ether, benzene, toluene and the like.

The reaction temperature of this reaction is not critical and thereaction is preferably carried out from under cooling to at ambienttemperature.

Process O: (XXII)→(XXIII)

The object compound (XXIII) can be prepared by reacting the compound(XXII) with ozone (1st step) and then degrading the resultant ozonide ina conventional manner (2nd step) and then reacting the resultantcompound with an oxidizing agent (3rd step) and then treating theresultant compound with an alcohol (4th step) (The First Method); or byreacting the compound (XXII) with an oxidizing agent (The SecondMethod).

Reaction Conditions of the 1st and 2nd steps of the First Method(Ozonolysis and degradation of ozonide) are substantially the same asthose of the Process C-2 as mentioned above and therefore are to bereferred to those of the Process C-2. It is to be noted that the 2ndstep is not essential for the preparation of the object compound (XXIII)and it is possible that the ozonide obtained by the 1st step can besubjected directly to the 3rd step.

The oxidizing agent to be used in the 3rd step of the First Method mayinclude an organic peracid (e.g. m-chloroperbenzoic acid, peraceticacid, etc.), hydrogen peroxide and the like.

The reaction of the 3rd step is usually carried out in the presence ofor absence of a conventional solvent which does not adversely influencethe reaction.

The reaction temperature of the 3rd step is not critical and thereaction is preferably carried out from under cooling to under heating.

The alcohol to be used in the 4th step of the First Method may includean alkanol (e.g. methanol, etc.) and the like.

The reaction of the 4th step is usually carried out without solvent atambient temperature to under heating.

The oxidizing agent to be used in the Second Method may includepotassium permanganate, a combination of potassium permanganate andsodium periodate, Ruthenium tetraoxide, a combination of Rutheniumtetraoxide and sodium periodate, and the like.

The reaction of the Second Method is usually carried out in aconventional solvent which does not adversely influence the reactionsuch as acetone, methyl ethyl ketone, aqueous acetone and the like.

Process P-1: (XXIII')→(XXIV)

The compound (XXIV) or a salt thereof can be prepared by reacting thecompound (XXIII') or a salt thereof with malonic acid or its derivativeor a salt thereof.

Suitable salt of the malonic acid or its derivative may include the samesalt with a base as that for the compound (I).

Suitable derivative of the malonic acid may include mono- or di-estersuch as exemplified in the explanation of "protected carboxy group".

The reaction can be carried out in a conventional solvent such asdioxane, tetrahydrofuran, N,N-dimethylformamide or any other organicsolvents which do not adversely influence the reaction, or a mixturethereof, in the presence of a condensing agent such as carbodiimidecompounds (e.g. N,N'-diethylcarbodiimide, N,N-diisopropylcarbodiimide,N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide,);N,N'-carbonylbis-(2-methylimidazole); keteneimine compounds (e.g.pentamethyleneketene-N-cyclohexylimine,diphenylketene-N-cyclohexylimine,); ethoxyacetylene;1-alkoxy-1-chloroethylene; ethyl polyphosphate; isopropyl polyphosphate;phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalylchloride; a combination of triphenylphosphine with carbon tetrachlorideor diazenedicarboxylate; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorus oxychloride, etc.; or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under from cooling to warming.

Process P-2: (XXIV)→(XXV)

The compound (XXV) or a salt thereof can be prepared by reacting thecompound (XXIV) or a salt thereof with acid azide.

Suitable acid azide may include arenesulfonyl azide which may havesubstituent (e.g. benzenesulfonyl azide, p-toluenesulfonyl azide,p-carboxybenzenesulfonyl azide, etc.), lower alkanesulfonyl azide (e.g.methanesulfonyl azide, ethanesulfonyl azide, etc.), and the like.

The reaction is usually carried out in a conventional solvent such astetrahydrofuran, dioxane, methylene chloride, acetonitrile,N,N-dimethylformamide or any other organic solvents which do notadversely influence the reaction, or a mixture thereof, in the presenceof an inorganic or organic base such as an alkali metal bicarbonate(e.g. sodium bicarbonate, potassium bicarbonate, etc.), alkali metalcarbonate (e.g. sodium carbonate, potassium carbonate, etc.), alkalineearth metal carbonate (e.g magnesium carbonate, calcium carbonate,etc.), tri(lower)alkylamine (e.g. trimethylamine, triethylamine,N,N-diisopropyl-N-ethylamine, etc.), pyridine compounds (e.g. pyridine,picoline, lutidine, N,N-di(lower)alkylaminopyridine such asN,N-dimethylaminopyridine, etc.), quinoline, N-lower alkylmorphorine(e.g. N-methylmorphorine, etc.), N,N-di(lower)alkylbenzylamine (e.g.N,N-dimethylbenzylamine, etc.), and the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under from cooling to warming.

Process P-3: (XXV)→(XXVI)

The compound (XXVI) or a salt thereof can be prepared by subjecting thecompound (XXV) or a salt thereof to cyclization.

The reagent used in this cyclization reaction may include metal (e.g.cupper, etc.), metallic acetate (e.g. lead acetate, palladium acetate,rhodium acetate, cupric acetate, etc.), metallic sulfate (e.g. cupricsulfate, etc.), and the like.

The reaction is usually carried out in a conventional solvent such asbenzene, toluene, tetrahydrofuran, dioxane, acetonitrile or any otherorganic solvents which do not adversely influence the reaction, or amixture thereof.

The reaction temperature is not critical, and the reaction is usuallycarried out from at ambient temperature to heating.

Process Q (XXVI)→(XXVII)→(XXVIII)→(XXIX) or (XXX)

The compound (XXVII) or a salt thereof can be prepared by reacting thecompound (XXVI) or a salt thereof with an acylating agent.

The present reaction can be carried out in a conventional acylationmanner.

Suitable acylating agents may be organic sulfonic or phosphoric acid orits reactive derivative such as acid halide, acid anhydride, and thelike, for example, diarylphosphoryl halide (e.g. diphenylphosphorylchloride, ditolylphosphoryl chloride, etc.), and the like.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,hexamethylphosphoramide, ethylene chloride, tetrahydrofuran, ethylacetate, dimethylsulfoxide, N,N-dimethylformamide, pyridine or any otherorganic solvents which do not adversely influence the reaction, or amixture thereof.

When the acylating agent is used in a free acid form or its salt form inthis reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent as exemplified in the explanation of theprocess P-1.

The reaction may also be carried out in the presence of an inorganic ororganic base as exemplified in the explanation of the process P-2.

The reaction temperature is not critical, and the reaction is usuallycarried out under from cooling to warming.

The compound (XXVII) or a salt thereof can be isolated in a conventionalmanner, but can also be used as the starting compound of the Second Stepwithout any isolation.

The compound (XXVIII) or a salt thereof can be prepared by reacting thecompound (XXVII) or a salt thereof with a thiol compound of the formula:R¹⁰ SH (R¹⁰ is the same as defined above) or a salt thereof.

Suitable salt of the thiol compound may include the same salt with abase as that for the compound (I).

The reaction is usually carried out in a conventional solvent such asthose given in the explanation of the First Step.

The reaction may also be carried out in the presence of an inorganic ororganic base such as those given in the explanation of the First Step.

The reaction temperature is not critical, and the reaction is usuallycarried out under from cooling to warming.

The compound (XXIX) or a salt thereof can be prepared by subjecting thecompound (XXVIII) or a salt thereof to removal reaction of theprotective group(s).

The present reaction is carried out in a conventional method such ashydrolysis, reduction, and the like.

Hydrolysis is preferably carried out in the presence of a base or anacid in a conventional manner.

The reaction temperature is not critical and the reaction is usuallycarried out under from cooling to warming.

The reduction method applicable for this removal reaction may include,for example, reduction by using a combination of a metal (e.g. zinc,zinc amalgam, etc.) or a salt of chrome compound (e.g. chromouschloride, chromous acetate, etc.) and an organic or inorganic acid (e.g.acetic acid, propionic acid, hydrochloric acid, sulfuric acid, etc.);and conventional catalytic reduction in the presence of a conventionalmetallic catalyst such as palladium catalysts (e.g. spongy palladium,palladium black, palladium oxide, palladium on carbon, colloidalpalladium, palladium on barium sulfate, palladium on barium carbonate,etc.), nickel catalysts (e.g. reduced nickel, nickel oxide, Raneynickel, etc.), platinum catalysts (e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.), and the like.

The reaction is usually carried out in a conventional solvent such aswater, alkanol (e.g. methanol, ethanol, propanol, etc.), dioxane,tetrahydrofuran, acetic acid or any other organic solvents which do notadversely influence the reaction, or a mixture thereof around a neutralcondition.

The reaction temperature is not critical, and the reaction is usuallycarried out under from cooling to warming.

The removal methods can be selected according to the kind of theprotective groups to be removed.

The compound (XXX) or a salt thereof can be prepared by oxidizing thecompound (XXVIII) or a salt thereof. The present oxidation reaction canbe carried out in a similar manner to that in Process O accordingly thereaction condition of present oxidation can be referred to that inProcess O.

The Preparations A to E are explained in detail as follows.

Preparation A: (II-1)→(II-2)

The compound (II-2) can be prepared by halogenating the compound (II-1).

The halogenating agent used in this reaction may include conventionalone which can be applied to converting a thio group into a halogen atomsuch as halogen (e.g. chlorine, bromine, etc.), sulfuryl halide (e.g.sulfuryl chloride, etc.), N-halosuccinimide (e.g. N-chlorosuccinimide,N-bromosuccinimide, etc.), and the like.

This reaction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as chloroform, methylenechloride, ethylene chloride, carbon tetrachloride, etc., or a mixturethereof.

The reaction temperature is not critical and the reaction is preferablycarried out from under cooling to at ambient temperature.

Preparation B: (II-3)→(II-2)

The object compound (II-2) can be prepared by halogenating the compound(II-3).

This reaction is substantially the same as Preparation A, and thereforethe halogenating agent, reaction conditions (e.g. reaction temperature,solvent, etc.) are referred to those of Preparation A.

Preparation C: (II-4)→(II-5)

The object compound (II-5) can be prepared by subjecting the compound(II-4) to introduction reaction of the hydroxy-protective group.

The introducing agent of the hydroxy-protective group used in thisreaction may include an organic carboxylic, carbonic and sulfonic acidor a reactive derivative thereof.

Suitable reactive derivative of the introducing agent may include, forexample, an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like, and preferably an acid chloride and acidbromide;

a mixed acid anhydride with an acid such as substituted phosphoric acid(e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoricacid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, alkyl carbonate (e.g., methyl carbonate, ethyl carbonate, propylcarbonate, etc.), aliphatic carboxylic acid (e.g. pivalic acid,pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroaceticacid, etc.), aromatic carboxylic acid (e.g., benzoic acid, etc.); asymmetrical acid anhydride; an activated acid amide with a heterocycliccompound containing imino function such as imidazole, 4-substitutedimidazole, dimethylpyrazole, triazole or tetrazole; an activated ester(e.g., p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyridyl ester, piperidinyl ester, 8-quinolylthioester, or an ester with a N-hydroxy compound such asN,N'-dimethylhydroxylamine, 1-hydroxy-2-(1H)pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole,1-hydroxy-6-chlorobenzotriazole, etc.), and the like.

The suitable reactive derivative can optionally be selected from theabove according to the kind of the compound (II-4) to be usedpreactically.

This introduction reaction is preferably carried out in the presence ofan organic or inorganic base such as alkali metal (e.g. lithium, sodium,potassium, etc.), alkaline earth metal (e.g. calcium, magnesium, etc.),alkali metal hydride (e.g. sodium hydride, etc.), alkaline earth metalhydride (e.g. calcium hydride, etc.), alkyl lithium (e.g. butyl lithium,etc.), lithium amide (e.g. lithium diisopropylamide, lithium isopropylcyclohexylamide, etc.), alkali metal hydroxide (e.g. sodium hydroxide,potassium hydroxide, etc.), alkali metal carbonate (e.g. sodiumcarbonate, potassium carbonate, etc.), alkali metal bicarbonate (e.g.sodium bicarbonate, potassium bicarbonate, etc.), alkali metal alkoxide(e.g. sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.),trialkylamine (e.g. triethylamine, etc.), pyridine compound (e.g.pyridine, lutidine, dimethylaminopyridine, picoline, etc.),N-alkylmorpholine (e.g. N-methylmorpholine, etc.), quinoline, and thelike.

The reaction is usually carried out in a conventional solvent which doesnot adversely influence the reaction such as water, acetone, dioxane,acetonitrile, chloroform, benzene, methylene chloride, ethylenechloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide,pyridine, hexamethylphosphoramide, etc., or a mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to at ambient temperature.

In this reaction, in case that the carboxylic acid or its reactivederivative is used as the introducing agent of the hydroxy-protectivegroup in the presence of diethyl azodicarboxylate, the configuration ofthe carbon atom on which the protected hydroxy group is often convertedto the other configuration, and such a case is also included within thescope of the present invention.

Preparation D: (II-5)→(II-4)

The object compound (II-4) can be prepared by removing thehydroxy-protective group from the compound (II-5).

This removal reaction can be carried out by hydrolysis as explained inProcess B-1, and therefore the reaction conditions (e.g. reactiontemperature, solvent, etc.) are referred to those of Process B-1.

Preparation E: (III-1)→(III-2)

The object compound (III-2) can be prepared by introducing acarboxy-protective group into the compound (III-1).

The introducing agent of a carboxy-protective group used in thisreaction may include a conventional esterifying agent which can convertthe carboxy group to the esterified group as exemplified before, forexample, alcohol or its reactive equivalent such as halide (e.g.chloride, bromide, iodide), sulfonate, sulfate, diazo compound, and thelike.

This reaction is usually carried out in the presence of a base asaforementioned in Preparation C, in a conventional solvent which doesnot adversely influence the reaction such as N,N-dimethylformamide,tetrahydrofuran or a mixture thereof.

The reaction temperature is not critical and the reaction is carried outunder cooling to at ambient temperature.

It is to be noted that, in the aforementioned reactions including theProcesses A to O and Preparation A to E and/or the post-treatment of thereaction mixture, in case that the compound possesses optical isomer, itmay occasionally be transformed into the other optical isomer and suchcase is also included within the scope of the present invention.

In case that the object compounds have a free carboxy group, forexample, in R³ and/or free amino group, for example, in R_(a) ¹, it maybe transformed into its salts by a conventional method.

The object compounds and salts thereof (I) of the present invention arenovel and useful intermediates for preparing antibiotics having thefundamental skeleton of Thienamycin, especially optically activeskeleton, which are highly active against a number of pathogenicmicroorganisms.

For example, the object compounds (I-4), (I-8), (I-11), (I-12), (I-13),(V-4) to (V-6), (IX-2), (X), (XV), (XXI) and (XXIII) in Processes B toE, F, G and I to O can be transformed into useful antibiotics having thefundamental skeleton of Thienamycin by the methods as shown in thefollowing literatures.

H. Onoue, et. al. Tetrahedron Letters No. 40, page 3867 (1979);

A. J. Gilby, et. al. German Offenlegungsschrift No. 28 11 514;

Eiji Oki, et. al. Japan Kokai No. 73656/1980;

David B. R. Johnston, et. al. Journal of the American Chemical Society,Volume 100, Page 313 (1978);

L. D. Cama, et. al. Journal of the American Chemical Society, Volume102, page 6161 (1980); and

L. D. Cama, et. al. Journal of the American Chemical Society, Volume100, page 8006 (1978).

F. A. Bouffard et.al. Journal of the Organic Chemistry, Volume 45, page1130 (1980);

S. M. Schmitt et.al. ibid, Volume 45, page 1135 and 1142 (1980);

Japan Kokai No. 5478/81;

T. Kametani et. al. Journal of the Amirican Chemical Society, Volume102, page 2060 (1980);

D. G. Melillo et.al. Tetrahedron Letters, Volume 21, page 2783 (1980);

T. Kametani et. al. Journal of the Chemical Society, Perkin I page 964(1981);

T. Kametani et. al. Heterocycles, Volume 14, page 1305 (1980);

T. Kametani et. al. Heterocycles, Volume 14, page 1967 (1980); and JapanKokai No. 22676/55

Further, the object compounds (XXIII') to (XXVII) or their salts areuseful intermediates for preparing a carbapenam compound such as theobject compounds (XXVIII), (XXIX) or their salts which have an excellentantimicrobial activity against pathogenic microorganisms and thereforeare useful as a therapeutic agent for human or animal infectiousdiseases.

The following test data show an antimicrobial activity of therepresentative compound of the carbapenem compounds (XXVIII) and (XXIX).

TEST METHOD

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (HI-agar) containing graded concentrations of antibiotics,and the minimal inhibitory concentration (MIC) was expressed in terms ofμg/ml after incubation at 37° C. for 20 hours.

TEST COMPOUND

Potassium(5R,6R)-3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate.

TEST RESULT

    ______________________________________                                        Test organisms    MIC (μg/ml)                                              ______________________________________                                        Staphylococcus aureus 6                                                                         1.56                                                        Pseudomonas aeruginosa                                                                          12.50                                                       NCTC-10490                                                                    ______________________________________                                    

The following Preparations and Examples are given for the purpose ofillustrating this invention.

PREPARATION 1

A solution of benzyl2-[(3R,4R)-4-methylthio-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(2.25 g) in methylene chloride (12 ml) was cooled to -78° C. and asolution of chlorine (390 mg) in carbon tetrachloride (3.4 ml) wasadded. After stirring for 30 minutes at the same temperature, themixture was warmed to 0° C. and evaporated to leave an oil (2.52 g). A2.10 g portion of this oil was chromatographed on silica gel (20 g)eluting with 10% ethyl acetate in methylene chloride to give benzyl2-[(3R,4S)-4-chloro-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(1.80 g) as an oil.

I.R. (CH₂ Cl₂): 1790, 1780 (shoulder), 1725 cm⁻¹.

N.M.R. (CDCl₃)δ: 2.07 (s, 3H), 2.30 (s, 3H), 5.27 (s, 2H), 5.50 (d,J=1.5 Hz, 1H), 6.17 (d, J=1.5 Hz, 1H).

PREPARATION 2

A solution of benzyl (6S)-6-phthalimidopenitillanate (610 mg) inmethylene chloride (5 ml) was cooled to -25° C. and a solution ofchlorine (465 mg) in carbon tetrachloride (3 ml) was added. Afterstirring for 45 minutes at the same temperature, the mixture was warmedto 0° C. and concentrated. The concentrate was poured into a cold,dilute aqueous sodium bicarbonate and extracted with ethyl acetate. Theextract was washed with brine, dried over magnesium sulfate andevaporated to leave an oil (700 mg), which was chromatographed on silicagel (10 g) eluting with 10% ethyl acetate in methylene chloride to givebenzyl2-[(3S,4R)-4-chloro-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(433 mg) as an oil.

I.R. (CH₂ Cl₂): 1790, 1780 (shoulder), 1725 cm⁻¹.

N.M.R. (CDCl₃) δ: 2.07 (s, 3H), 2.30 (s, 3H), 5.27 (s, 2H), 5.50 (d,J=1.5 Hz, 1H), 6.17 (d, J=1.5 Hz, 1H).

PREPARATION 3

A solution of methyl (6S)-6-phthalimidopenicillanate (9.01 g) inmethylene chloride (50 ml) was cooled to -30° C. and a solution ofchlorine (5.33 g) in carbon tetrachloride (30 ml) was added. The mixturewas stirred for 40 minutes, during which time the temperature was raisedto -10° C. After removal of the solvent by evaporation, the residue wasdissolved in ethyl acetate (100 ml) and washed with dilute aqueoussodium bicarbonate and water. Drying over magnesium sulfate andevaporation gave an oil, which was chromatographed on silica gel (100 g)eluting with 10% ethyl acetate in methylene chloride to give methyl2-[(3S,4R)-4-chloro-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(6.55 g) as a crystalline solid. mp. 122°-125° C.

I.R. (CH₂ Cl₂): 1785, 1675, 1720 cm⁻¹.

N.M.R. (CDCl₃) δ:2.13 (s, 3H), 2.37 (s, 3H), 3.90 (s, 3H), 5.62 (d, J=15Hz, 1H), 6.27 (d, J=15 Hz, 1H).

PREPARATION 4 ##STR6##

To a solution of methyl2-[(3S,4R)-3-{(1S)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(376 mg) and 4-dimethylaminopyridine (336 mg) in dichloromethane (3 ml)was added p-nitrobenzyl chloroformate (358 mg) at -30° C. under anitrogen atmosphere. After stirring for one hour at 0° C., the mixturewas diluted with ethyl acetate and washed with dilute hydrochloric acid,water, a dilute aqueous sodium bicarbonate, and brine. Drying overmagnesium sulfate and the removal of the solvent left an oil (635 mg),which was chromatographed on silica gel (25 g) eluting with 10-25% ethylacetate in hexane to afford methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate(566 mg) as an oil.

IR (CH₂ Cl₂): 1760, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.50 (d, J=7 Hz, 3H), 2.01 (s, 3H), 2.12 (s, 3H), 2.22(s, 3H), 3.43 (dd, J=5, 3 Hz, 1H), 3.73 (s, 3H), 4.94 (d, J=3 Hz, 1H),5.2 (m, 1H), 5.25 (s, 2H), 7.52 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H).

PREPARATION 5 ##STR7##

To a solution of a mixture (1:3) of methyl2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(1.84 g) and 4-dimethylaminopyridine (1.23 g) in dichloromethane (20 ml)was added a solution of p-nitrobenzyl chloroformate (1.60 g) indichloromethane (3 ml) at 0° C. After stirring at 0° C. for 1.5 hours,the mixture was diluted with ethyl acetate (150 ml) and washed withdilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate,and brine. Drying over magnesium sulfate and removal of the solvent leftan oil (3.1 g), which was chromatographed on silica gel (90 g) elutingwith 10-25% ethyl acetate in hexane to give a mixture (1:3) of methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate(2.90 g) as an oil.

IR (CH₂ Cl₂): 1755, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.51 (d, J=7 Hz, 1H), 2.01 (s, 3H), 2.12 (s, 3H), 2.23(s, 3H), 3.29 (dd, J=7, 3 Hz, 1/3H), 3.43 (dd, J=5, 3 Hz, 2/3H), 3.73(s, 3H), 4.95 (d, J=3 Hz, 2/3H), 5.02 (d, J=3 Hz, 1/3H), 5.2 (m, 1H),5.25 (s, 2H), 7.50 (d, J=9 Hz, 2H), and 8.16 (d, J=9 Hz, 2H)

PREPARATION 6 ##STR8##

To a solution of a mixture (5:1) of methyl2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(755 mg) and 4-dimethylaminopyridine (440 mg) in dichloromethane (6 ml)was added dropwise a solution of p-nitrobenzyl chloroformate (660 mg) indichloromethane (4 ml) during three minutes period at 0° C. After 1.5hours, the solution was concentrated, taken up into ethyl acetate (40ml), and washed with dilute hydrochloric acid, water and brine. Theorganic layer was dried over magnesium sulfate and evaporated to leavean oil. Chromatography on silica gel (50 g) eluting with 2-10% ethylacetate in dichloromethane to give methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate(974 mg).

IR (CH₂ Cl₂): 1760, 1720, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.50 (d, J=7 Hz, 1H), 2.01 (s, 3H), 2.12 (s, 3H), 2.24(s, 3H), 3.30 (dd, J=2.5, 7 Hz, 1H), 3.85 (s, 3H), 5.05 (d, J=2.5 Hz,1H), 5.23 (quinted, J=7Hz, 1H), 5.25 (s, 2H), 7.50 (d, J=9 Hz, 2H), 8.19(d, J=9 Hz, 2H)

(1S) Isomer of the above compound (165 mg) was also afforded.

PREPARATION 7 ##STR9##

To a solution of methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]but-2-enoate(530 mg) in dichloromethane (6 ml) was added a solution of chlorine (106mg) in carbon tetrachloride (0.9 ml) at -78° C. The solution was allowedto warm to 0° C. during 30 minutes and cooled again to -78° C.Additional chlorine (59 mg) in carbon tetrachloride (0.5 ml) was added.The solution was allowed to warm to 10° C. during 30 minutes andevaporated in vacuo. The residue was chromatographed on silica gel (18g) eluting with 10-33% ethyl acetate in hexane to give methyl[(3S,4R)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(trans isomer) (215 mg) andmethyl[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-azetidin-1-yl]-3-methylbut-2-enoate(cis isomer) (210 mg).

The Trans isomer:

IR (CH₂ Cl₂): 1780, 1750, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.53 (d, J=7 Hz, 3H), 2.03 (s, 3H), 2.30 (s, 3H), 3.7 (m,1H), 3.74 (s, 3H), 5.2 (m, 1H), 5.28 (s, 2H), 5.81 (d, J=1.5 Hz, 1H),7.54 (d, J=10 Hz, 2H), 8.20 (d, J=10 Hz, 2H).

The cis isomer:

IR (CH₂ Cl₂): 1780, 1750, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.55 (d, J=7 Hz, 3H), 2.07 (s, 3H), 2.30 (s, 3H), 3.62(t, J=4.5 Hz, 1H), 3.76 (s, 3H), 5.3 (m, 3H), 5.95 (d, J=4.5 Hz, 1H),7.48 (d, J=10 Hz, 2H), 8.17 (d, J=10 Hz, 2H).

PREPARATION 8 ##STR10##

To a solution of a mixture (1:3) of methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate(1.30 g) in dichloromethane (13 ml) was added a solution of chlorine(211mg) in carbon tetrachloride (2.2 ml) at -78° C. The solution wasallowed to warm to 0° C. during 45 minutes and concentrated. The residuewas dissolved in ethyl acetate (30 ml) and washed with a chilled aqueoussodium bicarbonate (2.5 g), water, and brine. Drying over magnesiumsulfate and evaporation left an oil (1.30 g), which showed two spots onsilica gel thin layer chromatography (1:1 hexane/ethyl acetate). Theresidue was chromatographed on silica gel (40 g) eluting with 10-30%ethyl acetate in hexane to afford firstly a mixture (5:6:4) of methyl2-[(3S)-4-chloro-3-{1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbutenoate[a mixture (5:6:4) of (1S,4R) isomer, (1R, 4R) isomer and (1R, 4S)isomer] (550 mg).

Further elution with 30% ethyl acetate in hexane and evaporation gave acrystalline solid (407 mg). Crystallization from a mixture ofdichloromethane and diethyl ether furnished methyl2-[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(270 mg), mp 154°-157° C.

IR (nujol): 1770, 1745, 1715 cm⁻¹.

NMR (CDCl₃ -d₁) δ: 1.55 (d, J=7 Hz, 3H), 2.07 (s, 3H), 2.29 (s, 3H),3.65 (t, J=4.5 Hz, 1H), 3.74 (s, 3H), 5.3 (m, 3H), 5.96 (d, J=4.5 Hz,1H), 7.50 (d, J=10 Hz, 2H), 8.18 (d, J=10 Hz, 2H); Mass spectrum: m/e442, 440 (M⁺).

PREPARATION 9 ##STR11##

To a solution of a mixture (1:3) of methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-azetidin-1-yl]but-2-enoate(527 mg) in dichloromethane (5.5 ml) was added a solution of chlorine(91 mg) in carbon tetrachloride (1.62 ml) at -78° C. The solution wasallowed to warm to 0° C. during one hour and evaporated. In order toremove sulfur derived as by-product, the residue was dissolved in carbontetrachloride (5 ml) and the solution was evaporated in vacuo. Thisprocedure was repeated once and the residue was pumped to leave theisomeric mixture of chlorides (588 mg) described in Preparation 8.

NMR (CDCl₃) δ: 1.5 (m, 3H), 2.02 (s, ˜1.5H), 2.07 (s,˜1.5H) 2.29 (s,3H), 3.7 (m, 4H), 5.3 (m, 3H), 5.81 (d, J=1.5 Hz, ˜0.25H), 5.86 (d,J=1.5 Hz, ˜0.15H), 5.97 (d, J=4.5 Hz, ˜0.6H), 7.5 (m, 2H), 8.21 (d, J=10Hz, 2H)

The residue (536 mg) was crystallized from diethyl ether to give crudecrystals (190 mg). Recrystallization from a mixed solvent ofdichloromethane and diethyl ether afforded methyl2-[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(170 mg). The mother liquors were combined and chromatographed on silicagel (9 g) eluting with 10-30% ethyl acetate in hexane to give a mixtureof methyl2-[(3S)-4-chloro-3-{1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[a mixture (5:3:2) of (1S,4R) isomer, (1R,4R) isomer and (1R,4S) isomer](231 mg) as an oil.

IR (CH₂ Cl₂): 1775, 1745, 1725 cm⁻¹.

NMR (CDCl₃) δ: 1.52 (d, J=7 Hz, 3H), 2.03 (s, 3H), 2.30 (s, 3H), 3.6-3.8(m, 4H), 5.25 (m, 1H), 5.27 (s, 2H), 5.81 (d, J=1.5 Hz, 0.5H), 5.86 (d,J=1.5 Hz, 0.3H), 5.98 (d, J=4.5 Hz, 0.2H), 7.5 (a pair of d, J=10 Hz,2H), 8.22 (d, J=10 Hz, 2H).

Further elution with 30% ethyl acetate in hexane recovered methyl2-[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(43 mg).

PREPARATION 10 ##STR12##

To a solution of methyl3-methyl-2-[(3S,4R)-4-methylthio-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]but-2-enoate(481 mg) in dichloromethane (5 ml) was added a solution of chlorine (83mg) in carbon tetrachloride (0.65 ml) at -78° C. The solution wasallowed to warm to 0° C. during 45 minutes and evaporated in vacuo. Theresidue was chromatographed on silica gel (12 g) eluting with 10-33%ethyl acetate in hexane to give methyl2-[(3S)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[a mixture (55:45) of (4R) isomer and (4S) isomer] (394 mg).

IR (CH₂ Cl₂): 1775, 1745, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.49 (d, J=7 Hz, 1.65H), 1.58 (d, J=7 Hz, 1.35H), 2.01(s, 3H), 2.29 (s, 3H), 3.65 (m, 1H), 3.73 (s, 1.65H), 3.75 (s, 1.35H),5.20 (m, 1H), 5.24 (s, 2H), 5.84 (d, J=1.5 Hz, 0.55H), 5.96 (d, J=4.5Hz, 0.45H), 7.49 (d, J=9 Hz, 2H), 8.18 (d, J=9 Hz, 2H).

PREPARATION 11 ##STR13##

To a solution of triphenylphosphine (1.647 g), formic acid (0.20 ml),and a mixture (1:3) of methyl2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(1.145 g) in tetrahydrofuran (14 ml) was added dropwise diethylazodicarboxylate (0.83 ml) at 0° C. under a nitrogen atmosphere. Afterkeeping at the same temperature for 15 minutes, the solution was allowedto warm to room temperature and stirred for two hours. The mixture wascooled to 0° C. and additional fornic acid (24 μl) and diethylazodicarboxylate (0.10 ml) were added. After stirring at roomtemperature for one hour, the solution was concentrated, taken up intoethyl acetate (60 ml) and washed with a chilled dilute aqueous sodiumbicarbonate, water, and brine. The organic layer was dried overmagnesium sulfate, evaporated and re-dissolved in benzene (20 ml) toresult in precipitation of crystals. These crystals were collected andwashed with benzene. The combined filtrate and washings were evaporatedand chromatographed on silica gel (60 g) eluting with 10-30% ethylacetate in hexane to give a mixture (5:1) of methyl2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(889 mg).

IR (CH₂ Cl₂): 1758, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.48 (d, J=7 Hz, 3H), 2.04 (s, 3H), 2.15 (s, 3H), 2.27(s, 3H), 3.31 (dd, J=2.5, 7 Hz, 1H), 3.81 (s, 3H), 4.97 (d, J=2.5 Hz,1/6H), 5.04 (d, J=2.5 Hz, 5/6H), 5.46 (quintet, J=7 Hz, 1H), 8.12 (s,1H).

PREPARATION 12 ##STR14##

To a solution of a mixture (5:1) of methyl2-[(3S,4R)-3-{(1RS)-1-formyloxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(880 mg) in methanol (20 ml) was added a 4.9M solution of sodiummethoxide in methanol (0.60 ml) at 0° C. After 30 minutes, acetic acid(0.20 ml) was added and the mixture was evaporated. The residue wastaken up into ethyl acetate (30 ml) and washed with a dilute aqueoussodium bicarbonate. Drying over magnesium sulfate and removal of thesolvent left an oil, which was chromatographed on silica gel (25 g)eluting with 5-20% acetone in dichloromethane to give a mixture (5:1) ofmethyl2-[(3S,4R)-3-}(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(742 mg).

IR (CH₂ Cl₂): 3560, 1750, 1715 cm⁻¹.

NMR (CDCl₃) δ: 1.34 (d, J=7 Hz, 3H), 2.01 (s, 3H), 2.14 (s, 3H), 2.23(s, 3H), 2.93 (br d, J=6 Hz, 1H), 3.16 (dd, J=2.5, 7 Hz 1H), 3.77 (s,3H), 4.22 (quintet, J=7 Hz, 1H), 4.92 (d, J=2.5 Hz, 1/6H), 5.06 (d,J=2.5 Hz, 5/6H).

PREPARATION 13 ##STR15##

To a solution of 3-(trimethylsilylmethyl)but-3-enoic acid (2.73 g) andtriethylamine (2.09 ml) in dimethylformamide (15 ml) was addedp-nitrobenzyl bromide (3.24 g) at 0° C. After stirring for four hours atthe same temperature, the mixture was poured into chilled dilutehydrochloric acid and extracted with a mixture of diethyl ether andethyl acetate (1:1, 150 ml). The extract was washed with water, a diluteaqueous sodium bicarbonate, water, and brine. Drying over magnesiumsulfate and removal of the solvent left an oil (3.90 g), which waschromatographed on silica gel (100 g) eluting with 20-50% hexane indichloromethane and then dichloromethane to give an oil (3.50 g).Distillation afforded p-nitrobenzyl 3-(trimethylsilylmethyl)but-3-enoate(3.25 g) bp˜160° C. (0.05 Torr).

IR (Film): 1735, 1630, 1605, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: ˜0.00 (s, 9H), 1.62 (s, 2H), 3.06 (s, 2H), 4.76 (br s,2H), 5.22 (s, 2H), 7.50 (d, J=9.5 Hz), 8.22 (d, J=9.5 Hz).

PREPARATION 14 ##STR16##

To a solution of 3-(trimethylsilylmethyl)but-3-enoic acid (36.5 g) indiethyl ether (200 ml) at 10°-15° C. was added a solution ofdiazomethane in diethyl ether (ca 0.6M solution, 400 ml). The excess ofdiazomethane was decomposed by addition of acetic acid. The resultantsolution was concentrated in vacuo to 200 ml and the concentrate waswashed with an aqueous sodium bicarbonate and brine. Drying overmagnesium sulfate and evaporation of the solvent left a yellow oil,which was distilled in vacuo to give methyl3-(trimethylsilylmethyl)but-3-enoate (34.74 g) as a colorless oil, bp74°-75° C. (10 Torr).

IR Film: 1735, 1635 cm⁻¹.

NMR (CCl₄) δ: 0.00 (s, 9H), 1.56 (s, 2H), 2.84 (s, 2H), 3.57 (s, 3H),4.60 (d, J=1.5 Hz, 1H), 4.65 (d, J=1.5 Hz, 1H).

PREPARATION 15 ##STR17##

A 0.9M solution of diethylaluminum chloride in hexane (24.4 ml) wasadded to a suspension of activated zinc powder (4.0 g) intetrahydrofuran (60 ml). After ten minutes the mixture was cooled to-20° C. A solution of methyl2-[(3S,4R)-3-bromo-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(6.16 g) and acetone (1.84 ml) in tetrahydrofuran (45 ml) was addeddropwise during 35 minutes at -20° C. under a nitrogen atmosphere. Theresulting mixture was stirred at -15° to -10° C. for 1.5 hours and at 0°C. for 30 minutes. The reaction was quenched by addition of pyridine (3ml). After ten minutes 2N hydrochloric acid (40 ml) and ethyl acetate(100 ml) were added. The mixture was filtered through diatomaceous earthand the filtrate was diluted with 2N hydrochloric acid (40 ml) and ethylacetate (100 ml). The mixture was shaken and the organic layer wasseparated. The aqueous layer was extracted with ethyl acetate (50 ml).The combined extracts were washed three times with brine, dried overmagnesium sulfate, and evaporated to give an oil (6.0 g). The residuewas chromatographed on silica gel (150 g, eluting with 2 to 25% acetonein dichloromethane) to give 3.79 g (66.0%) of methyl2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoateand 1.36 g of impure material. Rechromatography of the impure fractionon silica gel (100 g, eluting with 2 to 25% acetone in dichloromethane)afforded an additional 0.93 g (16.2%) of the desired product: IR(CH₂Cl₂): 3550, 1745, and 1715 cm⁻¹ ; NMR(CDCl₃)δ: 1.34 (s, 3H), 1.41 (s,3H), 2.00 (s, 3H), 2.13 (s, 3H), 2.21 (s, 3H), 2.56 (s, 1H), 3.14 (d,J=3 Hz, 1H), 3.75 (s, 3H), and 5.01 (d, J=3 Hz, 1H).

PREPARATION 16 ##STR18##

A 1.55N solution of n-butyl lithium in hexane (0.44 ml) was addeddropwise to a solution of methyl2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(164 mg) in tetrahydrofuran (2 ml) at -78° C. under a nitrogenatmosphere. After five minutes a solution of 4-nitrobenzyl chloroformate(147 mg) in tetrahydrofuran (1.5 ml) was added. The mixture was allowedto warm to 0° C. during 1.5 hours and stirred at the same temperaturefor 30 minutes. After being left at ambient temperature for 30 minutes,the reaction was quenched by addition of acetic acid (three drops). Themixture was evaporated, and the residue was taken up into ethyl acetate(20 ml) and washed in turn with a dilute aqueous solution of sodiumbicarbonate and brine. Drying over magnesium sulfate and removal of thesolvent left an oil which was chromatographed on silica gel (6.5 g;eluting with 1 to 2% ethyl acetate in dichloromethane for the desiredproduct followed by 20% acetone in dichloromethane for the startingmaterial) to give 170 mg of the desired product contaminated with someimpurities and 52 mg (31.7% recovery) of the starting material. Furtherpurification of the impure product on silica gel plates (20 cm×20 cm×2mm, two pieces; two developments with 2/1 hexane-ethyl acetate) afforded138 mg (51.8%; ie 83.4% based on consumed starting material) of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]but-2-enoate:IR(CH₂ Cl₂): 1750, 1720, 1520 and 1350 cm⁻¹ ; NMR (CDCl₃) δ; 1.64 (s,3H), 1.71 (s, 3H), 2.01 (s, 3H), 2.09 (s, 3H), 2.23 (s, 3H), 3.70 (1H,hidden), 3.75 (s, 3H), 5.07 (d, J=3 Hz, 1H), 5.20 (s, 2H), 7.57 (d, J=9Hz, 2H), and 8.18 (d, J=9 Hz, 2H).

PREPARATION 17 ##STR19##

A solution of chlorine (70 mg) in carbon tetrachloride (1.75 ml) wasadded to a solution of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]but-2-enoate(386 mg) in dichloromethane (4 ml) at -78° C. The mixture was allowed towarm to 0° C. during 40 minutes and evaporated. The residue wasdissolved in carbon tetrachloride (5 ml) and evaporated. This procedurewas repeated once and the residue was chromatographed on silica gel (8g, eluting with 10 to 30% ethyl acetate in hexane) to give a 4:1 mixtureof methyl2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[(3S,4R)-isomer] and its (3S,4S)-isomer: IR (CH₂ Cl₂): 1770, 1745, 1720,1520 and 1350 cm⁻¹ ; NMR (CDCl₃)δ: 1.67 (s, 2.4H), 1.74 (s, 2.4H), 1.79(s, 0.6H), 1.82 (s, 0.6H), 2.02 (s, 2.4H), 2.08 (s, 0.6H), 2.30 (s, 3H),3.74 (s, 2.4H), 3.75 (s, 0.6H), 3.93 (d, J=2 Hz, 0.8H), 4.02 (d, J=4 Hz,0.6H), 5.21 (s, 2H), 5.91 (d, J=2 Hz, 0.8H), 5.95 (d, partially hidden,0.2H), 7.53 (d, J=9 Hz, 2H), and 8.22 (d, J=9 Hz, 2H).

PREPARATION 18 ##STR20##

Methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]but-2-enoate(425 mg) was chlorinated in the same manner described above.Chromatography of the product on silica gel (10 g; eluting with 10 to30% ethyl acetate in hexane) afforded 294 mg (70.9%) of methyl2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[(3S,4R)-isomer] and 80 mg of the (3S,4S)-isomer contaminated someimpurities. Crystallization of the impure (3S,4S)-isomer from ether gave35 mg of the pure (3S,4S)-isomer.

Spectral Data the (3S,4R)-isomer: IR (CH₂ Cl): 1775, 1740, 1720, 1520and 1350 cm⁻¹ ; NMR (CDCl₃)δ: 1.66 (s, 3H), 1.71 (s, 3H), 2.02 (s, 3H),2.30 (s, 3H), 3.74 (s, 3H), 3.93 (d, J=2 Hz, 1H), 5.20 (s, 3H), 5.91 (d,J=2 Hz, 1H), 7.52 (d, J=8 Hz, 2H), and 8.20 (d, J=8 Hz, 2H).

the (3S,4S)-isomer: IR (CH₂ Cl₂): 1775, 1740, 1725, 1520, and 1350 cm⁻¹; NMR (CDCl₃)δ: 1.78 (s, 3H), 1.81 (s, 3H), 2.07 (s, 3H), 2.29 (s, 3H),3.74 (s, 3H), 4.00 (d, J=5 Hz, 1H), 5.18 (s, 2H), 5.93 (d, J=5 Hz, 1H),7.46 (d, J=9 Hz, 2H), and 8.16 (d, J=9 Hz, 2H).

PREPARATION 19 ##STR21##

To a solution of methyl2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(60 mg) in dichloromethane (2 ml) was added a solution of chlorine (24mg) in carbon tetrachloride (0.2 ml) at -50° C. The solution was allowedto warm to -10° C. during 30 minutes and cooled to -50° C. An additionalsolution of chlorine (12 mg) in carbon tetrachloride (0.1 ml) was added.The solution was allowed to warm to -5° C. and evaporated. The residuewas chromatographed on silica gel (1.5 g, eluting with 8-10% ethylacetate in hexane) to give 21.0 mg (36.1%) of methyl2-[(3S,4R)-3-[(1S)-1-(tert-butyldimethylsilyloxy)ethyl]-4-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate.NMR (CDCl₃)δ: 0.12 (s, 6H), 0.93 (s, 9H), 1.34 (d, J=6.5 Hz, 3H), 2.01(s, 3H), 2.29 (s, 3H), 3.56 (dd, J=1.5, 5 Hz, 1H), 3.77 (s, 3H), 4.30(dq, J=5, 6.5 Hz, 1H), 5.80 (d, J=1.5 Hz, 1H).

EXAMPLE 1 ##STR22##

A mixture of benzyl 2-[(3R,4S)-4-chloro-3-phthalimido-2-oxo-azetidin-1-yl]-3-methyl-2-butenoate(860 mg) and allyltrimethylsilane (0.48 ml) in methylene chloride (6 ml)was cooled to -78° C. and silver tetrafluoroborate (490 mg) was added.The mixture was stirred for 3 hours, during which time the temperaturewas gradually raised to room temperature. The reaction mixture wasdiluted with ethyl acetate and filtered by the aid of Celite. Thefiltrate was washed successively with water, dilute aqueous sodiumbicarbonate and brine, dried over magnesium sulfate and evaporated togive an oil (841 mg), which was chromatographed on silica gel (25 g)eluting with 10% ethyl acetate in methylene chloride to give benzyl2-[(3S,4S)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(445 mg) as an oil.

I.R. (CH₂ Cl₂): 1760, 1720, 1385 cm⁻¹.

N.M.R. (CDCl₃)δ: 2.10 (s, 3H), 2.25 (s, 3H), 2.43 (m, 2H), 4.38 (ddd,J=3, 6.5 Hz, 1H), 4.8-5.3 (m, 2H), 5.08 (d, J=3 Hz, 1H), 5.33 (s, 2H),5.56 (m, 1H).

EXAMPLE 2 ##STR23##

A mixture of methyl2-[(3S,4R)-4-chloro-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(3.55 g) and allyltrimethylsilane (2.26 ml) in methylene chloride (25ml) was cooled to -78° C., and silver tetrafluoroborate (2.29 g) wasadded. The mixture was stirred for 2 hours during which time thetemperature was gradually raised to 0° C., and the stirring wascontinued for another 3.5 hours. Saturated aqueous sodium chloride (10ml) was added to the reaction mixture and the pH value of the aqueouslayer was adjusted to pH 7 by adding saturated aqueous sodiumbicarbonate. After stirring for 20 minutes at 0° C., the precipitate wasfiltered off through a pad of Celite and the filtrate was separated intothe organic layer and the aqueous layer. The organic layer was washedwith brine, dried over magnesium sulfate and evaporated to leave an oil(4.0 g), which was chromatographed on silica gel (50 g) eluting with amixture of benzene and acetone (10:1) to give methyl2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(2.74 g) as an oil.

I.R. (CH₂ Cl₂) 1770 (shoulder), 1760, 1720 cm⁻¹.

N.M.R. (CDCl₃)δ: 2.11 (s, 3H), 2.26 (s, 3H), 2.4-2.6 (m, 2H), 4.40 (m,1H), 5.0-5.3 (m, 3H), 5.70 (m, 1H).

EXAMPLE 3 ##STR24##

Silver tetrafluoroborate (323 mg) was added to a stirred mixture ofmethyl2-[(3S,4R)-4-chloro-2-oxo-3-phthalimidoazetidin-1-yl]-3-methylbut-2-enoate(500 mg) and methyl 3-(trimethylsilylmethyl)-but-3-enoate (460 mg) indichloromethane (2.5 ml) at -78° C. under a nitrogen atmosphere. Thestirring mixture was gradually allowed to warm to 0° C. during one hourand kept at 0° C. for 1.5 hours. A saturated aqueous sodium chloride (2ml) was added and the heterogeneous mixture was brought to pH 7 with asaturated aqueous sodium bicarbonate. After stirring for 15 minutes, themixture was diluted with ethyl acetate and filtered through a pad ofCelite. The organic layer was separated, washed with brine, dried overmagnesium sulfate, and evaporated. The residue was chromatographed onsilica gel (10 g) eluting with a mixture of benzene and acetone (5:1).Further purification on a silica gel (10 g) eluting with 10-20% ethylacetate in dichloromethane) afforded methyl2-[(3R,4R)-4-[2-(methoxycarbonylmethyl)allyl]-2-oxo-3-phthalimidoazetidin-1-yl]-3-methylbut-2-enoate(483 mg) as an oil.

IR (CH₂ Cl₂): 1780 (sh), 1765, 1730 (sh), 1725 cm⁻¹.

NMR (CDCl₃)δ: 1.13 (3H, s), 1.27 (3H, s), 2.56 (2H, m), 3.01 (2H, s),3.62 (3H, s), 3.83 (3H, s), 4.56 (ddd, J=3,6,8 Hz, 1H), 4.96 (2H, br s),5.10 (d, J=3 Hz, 1H), 7.80 (4H, m).

EXAMPLE 4 ##STR25## (The symbol of "PNB" means a p-nitrobenzyl group.)

To a solution of methyl2-[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(222 mg) and methyl 3-(trimethylsilylmethyl)but-3-enoate (190 mg) indichloromethane (1.7 ml) was added silver tetrafluoroborate (146 mg) at-72° C. under a nitrogen atmosphere. The stirring mixture was graduallyallowed to warm to 0° C. during one hour and kept at the sametemperature for 30 minutes. The mixture was diluted with ethyl acetate(5 ml). A saturated aqueous sodium chloride (3 ml) was added and themixture was neutralized with a saturated aqueous sodium bicarbonate. Theresultant mixture was filtered through Celite and the solid was washedwith ethyl acetate. The organic layer was separated, washed with brine,dried over magnesium sulfate and evaporated. The residue waschromatographed on silica gel (8 g) eluting with 5-10% ethyl acetate indichloromethane to give an oil (220 mg). Further purification on asilica gel column chromatography (15 g) eluting with 10 to 40% ethylacetate in hexane afforded methyl2-[(3S,4R)-4-{2-(methoxycarbonylmethyl)allyl}-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(190 mg).

IR (CH₂ Cl₂): 1750, 1720 (sh), 1525, 1350 cm⁻¹.

NMR (CDCl₃)δ: 1.50 (3H, J=6.5 Hz, d), 1.96 (3H, s), 2.20 (3H, s),2.3-2.7 (2H, m), 3.04 (2H, s), 3.18 (1H, dd, J=2.5, 4.5 Hz), 3.68 (3H,s), 3.74 (3H, s), 4.08 (1H, ddd, J=2.5, 6, 8 Hz), 4.96 (2H, s), 5.14(1H, dd, J=4.5, 6.5 Hz), 5.25 (2H, s), 7.54 (2H, d, J=10 Hz), 8.18 (2H,d, J=10 Hz).

EXAMPLE 5 ##STR26##

To a solution of a mixture (5:3:2) of methyl2-[(3S,4R)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[(1S,3s)transisomer]and its (1R,3S-trans)-isomer and (1R,3S,cis)-isomer (191 mg), and methyl3-(trimethylsilylmethyl)-but-3-enoate (162 mg) in dichloromethane (1.5ml) was added silver tetrafluoroborate (127 mg) at -78° C. under anitrogen atmosphere. The stirring mixture was gradually allowed to warmto 0° C. during one hour and kept at the same temperature for 1.5 hours.A saturated aqueous solution of sodium chloride (2 ml) and ethyl acetate(5 ml) were added and the mixture was neutralized with a saturatedaqueous solution of sodium bicarbonate. After further dilution withethyl acetate (15 ml), the mixture was filtered through Celite. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate and evaporated. The residue was chromatographed on silica gel (8g) eluting with 1-5% acetone in dichloromethane to give an oil (141 mg).Further purification on a silica gel column chromatography (8 g) elutingwith 10 to 30% ethyl acetate in hexane afforded a mixture (1:1) ofmethyl2-[(3S,4R)-4-{2-(methoxycarbonylmethyl)allyl}-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (131 mg).

IR (CH₂ Cl₂): 1750, 1720 (sh), 1525, 1350 cm⁻¹.

NMR (acetone-d₆) δ: 1.42 (1.5H, d, J=7 Hz), 1.46 (1.5H, d, J=7 Hz), 1.94(3H, s), 2.14 (3H, s), 2.4-2.6 (2H, m), 3.07 (2H, s), 3.14 (0.5H, dd,J=3, 7 Hz), 3.24 (0.5H, dd, J=3, 5 Hz), 3.62 (3H, s), 3.72 (3H, s), 4.14(1H, m; t, J=2 Hz upon irradiation at 2.5 ppm), 4.9-5.1 (2H, m), 5.0-5.3(1H, m), 5.33 (2H, s), 7.69 (2H, brd, J=9 Hz), 8.24 (2H, d, J=9 Hz).

EXAMPLE 6 ##STR27##

In a similar manner to that described in Example 5, a mixture (5:6:4) ofmethyl2-[(3S,4R)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate[(1S,3S-trans)-isomer],(1R,3S-trans)-isomer and (1R,3S-cis)-isomer (270 mg) afforded a mixture(2:1) of methyl2-[(3S,4R)-4-{2-(methoxycarbonylmethyl)allyl}-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(193 mg).

NMR (acetone-d₆)δ: 1.43 (2H, d, J=6.5 Hz), 1.47 (1H, d, J=6.5 Hz), 1.95(3H, s), 2.15 (3H, s), 2.4-2.6 (2H, m), 3.08 (2H, s), 3.17 (2/3H, dd,J=3,7 Hz), 3.26 (1/3H, dd, J=3,5 Hz), 3.63 (3H, s), 3.73 (3H, s), 4.15(1H, m;t, J=2 Hz upon irradiation at 2.5 ppm), 4.9-5.1 (2H, m), 5.13(˜2/3H, quintet, J=7 Hz), ˜5.1 (˜1/3H, m), 5.34 (2H, s), 7.67 (2H, br d,J=9 Hz), 8.24 (2H, d, J=9 Hz).

EXAMPLE 7 ##STR28##

To a solution of methyl2-[(3S,4R)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(180 mg) and allyltrimethylsilane (0.12 ml) in dichloromethane (2 ml)was added silver tetrafluoroborate (240 mg) at -78° C. under a nitrogenatmosphere. The stirring mixture was allowed to warm to 0° C. during 45minutes and kept at the same temperature for one hour. The mixture wasdiluted with ethyl acetate (10 ml) and a saturated aqueous sodiumchloride was added. The mixture was neutralized with a saturated aqueoussodium bicarbonate, diluted with additional ethyl acetate (20 ml) andfiltered through a pad of cellurose powder. The organic layer wasseparated, washed with brine, dried over magnesium sulfate andevaporated. The residue was chromatographed on silica gel (11 g) elutingwith 3-30% ethyl acetate in dichloromethane to give methyl3-methyl-2-[(3S,4R)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-4-allylazetidin-1-yl]but-2-enoate(47 mg).

IR (CH₂ Cl₂): 1750, 1725, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.49 (3H, d, J=7 Hz), 1.95 (3H, s), 2.19 (3H, s), 2.1-2.6(2H, m), 3.17 (1H, dd, J=2.5, 5 Hz), 3.73 (3H, s), 3.90 (1H, ddd,J=2.5,6,8 Hz), 4.9-5.3 (3H, m), 5.24 (2H, s), 5.5-5.9 (1H, m), 7.51 (2H,d, J=9 Hz), 8.18 (2H, d, J=9 Hz).

EXAMPLE 8 ##STR29##

To a solution of benzyl2-[(3S,4S)-4-allyl-3-phthalimido-2-oxo-azetidin-1-yl]-3-methyl-2-butenoate(340 mg) in a mixture of methylene chloride (5 ml) and methanol (2.5 ml)was added N,N-dimethyl-1,3-propanediamine (0.21 ml) and the mixture wasstirred at room temperature for 25 hours. After removal of the solventby evaporation, the residue was dissolved in ethyl acetate and washedwith water. Drying over magnesium sulfate and evaporation gave an oil,which was chromatographed on silica gel (3 g) eluting with a mixture ofmethylene chloride and acetone (6:1) to give benzyl2-[(4S)-4-allyl-3-amino-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (155mg) as an oil.

I.R. (CH₂ Cl₂): 1750, 1710 cm⁻¹.

N.M.R. (CDCl₃) δ: 1.66 (broad s, 2H), 1.94 (s, 3H), 2.22 (s, 3H), 2.34(m, 2H), 3.5-3.8 (m, 2H), 4.9-5.3 (m, 4H), 5.62 (m, 1H).

EXAMPLE 9 ##STR30##

To a solution of methyl2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(2.64 g) in a mixture of methylene chloride (20 ml) and methanol (10 ml)was added N,N-dimethyl-1,3-propanediamine (1.98 ml) and the mixture wasleft in a refrigerator for 3 days and at room temperature for 24 hours.The reaction mixture was evaporated and the residue was dissolved inethyl acetate (50 ml), washed with water, dried over magnesium sulfateand evaporated to give an oil, which was chromatographed on silica geleluting with a mixture of methylene chloride and acetone (6-5:1) to givemethyl 2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(873 mg) as an oil.

IR (CH₂ Cl₂): 1755, 1720 cm⁻¹.

EXAMPLE 10 ##STR31##

To a solution of methyl2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(6.78 g) in a mixture of methylene chloride (46 ml) and methanol (23 ml)was added N,N-dimethyl-1,3-propanediamine (6.25 ml) at 0° C. and themixture was left at room temperature for 5 days. The reaction mixturewas evaporated and the residue was chromatographed on silica gel elutingwith a mixture of methylene chloride and ethyl acetate (10:1-5) to givemethyl2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(3.70 g) as an oil.

IR (CH₂ Cl₂): 1755, 1720 cm⁻¹.

NMR (CD₃ COCD₃) δ: 1.92 (3H, s), 1.15 (3H, s), 2.45 (broad t, 2H, J=6.5Hz), 3.73 (3H, s), 4.13 (d and t, 1H, J=6.5 Hz, 2.5 Hz), 4.58 (1H, d,J=2.5 Hz), 4.9-5.2 (2H, m), 5.5-6.0 (1H, m).

EXAMPLE 11 ##STR32##

A solution of benzyl2-[(4S)-4-allyl-3-amino-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (175mg) in methylene chloride (6 ml) was cooled to 0° C. and triethylaminehydrobromide (404 mg), isopentylnitrite (90 μl) and p-toluenesulfonicacid hydrate (190 mg) were added. After stirring for 30 minutes at thesame temperature, the reaction mixture was diluted with ethyl acetate(30 ml) and washed successively with dilute sodium bicarbonate, waterand brine. Drying ove magnesium sulfate and evaporation left an oil ofbenzyl 2-[(4S)-4-allyl-3-bromo-2-oxoazetidin-1-yl]-3-methyl-2-butenoate.

This oil was dissolved in methylene chloride (2 ml) and cooled to 15° C.To this cooled solution were added acetic acid (0.2 ml) and zinc powder(300 mg), and the mixture was stirred for 30 minutes at the sametemperature. The reaction mixture was diluted with ethyl acetate (30 ml)and filtered by the aid of Celite. The filtrate was washed successivelywith dilute aqueous sodium bicarbonate, water and brine. Drying overmagnesium sulfate and evaporation gave an oil, which was purified bypreparative thin layer chromatography (silica gel plate, developpingsolvent: 10% ethyl acetate in methylene chloride) to give benzyl2-[(4S)-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (40 mg) as anoil.

I.R. (CH₂ Cl₂): 1750, 1720 cm⁻¹.

N.M.R. (CDCl₃) δ: 1.94 (s, 3H), 1.18 (s, 3H), 2.30 (m, 2H), 2.77 (ABpart of an ABX pattern, J_(AB) =15 Hz, J_(AX) =5 Hz, J_(BX) =2 Hz, 2H),3.90 (m, 1H), 4.92 (m, 1H), 5.04 (m, 1H), 5.16 (ABq, J=12 Hz), 5.56 (m,1H).

EXAMPLE 12 ##STR33##

A mixture of methyl2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (815mg), triethylamine hydrobromide (2.50 g) and p-toluenesulfonic acidhydrate (1.17 g) in methylene chloride (30 ml) was cooled to 0° C. andisopentyl nitrite (0.54 ml) was added. After stirring for 20 minutes atthe same temperature, the mixture was concentrated and the residue wasdissolved in ethyl acetate (50 ml). The solution was washed successivelywith 10% aqueous sodium bisulfite, water and brine, dried over magnesiumsulfate and evaporated to give methyl2-[(4R)-3-bromo-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (840mg) as a crude oil.

I.R. (CH₂ Cl₂): 1770, 1725 cm⁻¹.

EXAMPLE 13 ##STR34##

A solution of methyl2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.0g) in methylene chloride (10 ml) was cooled to -65° C., andisopentylnitrite (1.01 ml) and a solution of hydrogen chloride (524 mg)in ethyl ether (8 ml) were added. The mixture was allowed to warm to 0°C. during a period of 45 minutes and stirred for one hour and half at 0°C. The reaction mixture was poured into a mixture of ethyl acetate (40ml) and dilute aqueous sodium bicarbonate. The organic layer wasseparated and washed with brine, dried ove magnesium sulfate andevaporated to leave an oil, which was chromatographed on silica gel (15g) eluting with a mixture of methylene chloride and acetone(100:2-100:5) to give methyl2-[(4R)-4-allyl-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (658mg) as an oil.

IR (CH₂ Cl₂): 1775, 1720 cm⁻¹.

NMR (CDCl₃) δ: 2.00 (3H, s), 2.24 (3H, s), 2.2-2.7 (2H, m), 3.78 (a pairof singlets, 3H), 4.0-4.5 (2H, m), 4.9-5.3 (2H, m), 5.5-5.9 (1H, m).

EXAMPLE 14 ##STR35##

Methyl 2-[(4R)-3-bromo-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate(840 mg) was dissolved in methylene chloride (6 ml) and cooled to 5° C.To this cooled solution were added acetic acid (0.5 ml) and zinc powder(0.60 g), and the mixture was allowed to warm to room temperature. Afterstirring for 30 minutes, the reaction mixture was diluted with ethylacetate (6 ml) and filtered through a pad of Celite. The filtrate wasfurther diluted with ethyl acetate (50 ml) and washed successively withwater, dilute sodium bicarbonate and brine. Drying over magnesiumsulfate and evaporation left an oil, which was chromatographed on silicagel (20 g) eluting with a mixture of benzene and acetone (5:1) to givemethyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (174 mg)as an oil.

IR (CH₂ Cl₂): 1745, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.96 (3H, s), 2.18 (3H, s), 2.2-2.5 (2H, m), 2.88 (ABpart of a ABA system, J_(AB) =16 Hz, J_(AX) =2.5 Hz, J_(BX) =5 Hz, 2H),2.75 (3H, s), 3.96 (1H, m), 5.00 (1H, m), 5.14 (1H, m), 5.72 (1H, m).

EXAMPLE 15 ##STR36##

A mixture of methyl2-[(4R)-4-allyl-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (600mg), tributyltinhydride (0.97 ml) and2,2'-azobis-(2-methylpropionitrile) (40 mg) in benzene (16 ml) wasrefluxed for 1.5 hours. The reaction mixture was poured into a mixtureof ethyl acetate (30 ml) and dilute aqueous sodium bicarbonate. Theorganic layer was separated, and washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The oily residue was chromatographed onsilica gel (10 g) eluting with a mixture of hexane and ethyl acetate(10:1-10:3) to give methyl2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (452 mg) as anoil.

IR (CH₂ Cl₂): 1750, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.97 (3H, s), 2.20 (3H, s), 2.3-2.5 (2H, m), 2.63 (dd,1H, J=3 Hz, 16 Hz), 3.11 (dd, 1H, J=5 Hz, 16 Hz), 3.77 (3H, s), 3.7-4.2(1H, m), 4.8-5.3 (2H, m), 5.4-6.1 (1H, m).

EXAMPLE 16 ##STR37##

A mixture of methyl2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (100 mg),palladium chloride (16 mg) and cuprous chloride (44 mg) in a mixture ofdimethylformamide (1 ml) and water (0.12 ml) was stirred under an oxygenatmosphere for 3.5 hours. The reaction mixture was diluted with ethylacetate (20 ml), and filtered. The filtrate was washed with water andbrine. The combined aqueous layer was extracted with ethyl acetate (10ml×2) and the extract was washed with brine. The organic layers werecombined, and dried over magnesium sulfate, and evaporated in vacuo. Theoily residue was chromatographed on silica gel (1 g) eluting withmethylene chloride and acetone (100:2-100:5) to give methyl2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (89 mgas an oil.

IR (CH₂ Cl₂): 1745, 1710 cm⁻¹.

NMR (CDCl₃) δ: 1.92 (3H, s), 2.13 (3H, s), 2.18 (3H, s), 2.4-3.4 (4H,m), 3.76 (3H, s), 4.2-4.5 (1H, m).

EXAMPLE 17 ##STR38##

Ozone was bubbled through a solution of methyl2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (580mg) in ethyl acetate (10 ml) at -65° C. until the color of the mixtureturned into blue. The nitrogen was bubbled through the mixture at thesame temperature for 15 minutes. The reaction mixture was diluted withethyl acetate (30 ml) and the solution was treated with brine whichcontained sodium bicarbonate (1.26 g). The separated water layer wasextracted with ethyl acetate (20 ml). The organic layers were combinedand dried over magnesium sulfate and evaporated in vacuo to give methyl[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-glyoxylate. This product wasdiluted with methylene chloride (5 ml) and cooled to 0° C., and thenzinc powder (1.06 g) and acetic acid (0.5 ml) were added. After stirringfor 2 hours at room temperature, zinc powder (580 mg) and acetic acid(0.25 ml) were added and the mixture was stirred for 2 hours at roomtemperature. The mixture was filtered and the filtrate was evaporated invacuo. The residue was diluted with methylene chloride, and washed withbrine, and the water layer was extracted with ethyl acetate two times.The organic layers were combined, dried over magnesium sulfate andevaporated in vacuo to give methyl2-hydroxy-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate (300 mg) asan oil.

IR (CH₂ Cl₂): 1760, 1710 cm⁻¹.

NMR (CDCl₃) δ: 2.19 (3H, s), 2.2-3.4 (4H, m), 3.80 (3/4H, s), 3.88(9/4H, s), 4.04-4.4 (1H, m).

EXAMPLE 18 ##STR39##

A solution of methyl2-hydroxy-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate (268 mg) intetrahydrofuran (5 ml) was cooled to -40° C. 2,6-Lutidine (0.287 ml) andthionyl chloride (0.18 ml) were added, and the mixture was stirred forone hour, during which time the temperature was allowed to warm to 0° C.The mixture was filtered and the filtrate was concentrated in vacuo togive methyl 2-chloro-2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]acetate.This product was diluted with benzene and concentrated in vacuo again.The residue was diluted with tetrahydrofuran (5 ml), and 2,6-lutidine(0.287 ml) and triphenylphosphine (650 mg) were added at 0° C. Themixture was stirred at room temperature for 15 hours, and filtered. Thefiltrate was concentrated in vacuo and the residue was chromatographedon silica gel (10 g) eluting with a mixture of ethyl acetate and acetone(10:1-10:5) to give methyl2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-2-(triphenylphosphoranylidene)acetate(350 mg) as an oil.

IR (CH₂ Cl₂): 1735, 1705 cm⁻¹.

EXAMPLE 19 ##STR40##

A solution of methyl2-[(4R)-4-(2-oxopropyl)-2-oxoazetidin-1-yl]-2-(triphenylphospharanylidene)acetate(100 mg) in toluene (3 ml) was stirred at 110° C. for 2 hours. Themixture was concentrated in vacuo and the residue was chromatographed onsilica gel (3 g) eluting with a mixture of benzene and acetone (10:1) togive methyl(5R)-3-methyl-7-oxo-1-azabicyclo-[3,2,0]-hept-2-en-2-carboxylate (17mg).

IR (CHCl₃): 1770, 1720 cm⁻¹.

NMR (Benzene-d₆) δ: 1.7-2.0 (2H, m), 1.85 (3H, s), 2.12 (dd, 1H, J=3 Hz,15 Hz), 2.66 (dd, 1H, J=7 Hz, 15 Hz), 3.1-3.5 (1H, m), 3.48 (3H, s).

EXAMPLE 20 ##STR41##

A mixture of methyl2-[(3R,4R)-4-{2-(methoxycarbonylmethyl)allyl}-2-oxo-3-phthalimidoazetidin-1-yl]-3-methylbut-2-enoate(103 mg) and N,N-dimethyl-1,3-propanediamine (60 μl) in a mixture ofdichloromethane (0.7 ml) and methanol (0.7 ml) was stirred at roomtemperature for 6.5 days. The resultant solution was concentrated invacuo and the residue was chromatographed on silica gel (1.5 g) elutingwith dichloromethane, 30% ethyl acetate in dichloromethane, and 5%methanol in dichloromethane to give an oil (55 mg). Further purificationon a silica gel plate (developing solvent: 7% methanol indichloromethane) afforded a mixture (10:7) of methyl2-[(3R,4R)-3-amino-4-{2-(methoxycarbonylmethyl)allyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoateand methyl2-[(3R,4R)-3-amino-4-{3-(methoxycarbonyl)-2-methylally}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(47 mg) as an oil.

IR (CH₂ Cl₂): 1750, 1735 (sh), 1720 cm⁻¹.

NMR (CDCl₃) δ: 5.05 (m, 20/17H), 5.75 (br s 7/17H).

EXAMPLE 21 ##STR42##

To a solution of methyl2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (500mg) in dichloromethane (5 ml) was added acetic formic anhydride (0.34ml) at 0°. After stirring at the same temperature for one hour, themixture was diluted with ethyl acetate (35 ml) and washed with a diluteaqueous sodium bicarbonate. The aqueous layer was saturated with sodiumchloride and extracted with dichloromethane. The extracts were combined,washed with a saturated aqueous sodium chloride, dried over magnesiumsulfate and evaporated. The residue was chromatographed on silica gel(2.5 g) eluting with 10-30% acetone in dichloromethane afforded methyl2-[(3R,4R)-3-formamido-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(485 mg).

IR (CH₂ Cl₂): 3400, 1760, 1720 (sh), 1695 cm⁻¹.

NMR (CDCl₃) δ: 1.97 (s, 3H), 2.21 (s, 3H), 2.47 (t, J=7 Hz, 2H), 3.76(s, 3H), 3.95 (dt, J=3, 7 Hz, 1H), 4.77 (dd, J=3, 7 Hz, 1H), 4.9-5.3 (m,2H), 5.5-6.0 (m, 1H), 7.15 (brd, J=7 Hz, 1H), 8.19 (s, 1H).

Mass Spectrum: m/e 266 (M⁺).

EXAMPLE 22 ##STR43##

2,6-Lutidine (3.82 ml) and phosphorus oxychloride (1.37 ml) were addedto a solution of methyl2-[(3R,4R)-3-formamido-2-oxo-4-allylazetidin-1yl]-3-methylbut-2-enoate(970 mg) in dichloromethane (10 ml) at 0° C., and the mixture wasstirred for three hours at 0° C. Then, the reaction mixture was pouredinto a mixture of ethyl acetate (100 ml) and brine (50 ml). The organiclayer was washed with brine, dried over magnesium sulfate and evaporatedin vacuo. The oily residue was chromategraphed on silica gel (15 g)eluting with a mixture of hexane and ethyl acetate (10:1-3:1) to givemethyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(766 mg) as an oil.

I.R. (CH₂ Cl₂): 2145, 1775, 1720 cm⁻¹.

N.M.R. (CDCl₃) δ: 1.96 (s, 3H), 2.24 (s, 3H) 2.3-2.6 (m, 2H), 3.80 (s,3H), 4.20 (dt, 1H, J=2.5, 6.5 Hz), 4.98 (d, 1H, J=2.5 Hz), 5.0-5.3 (m,2H, 5.5-6.0 (m, 1H).

Mass Spectrum: m/e 248 (M⁺).

EXAMPLE 23 ##STR44##

2,2'-Azobis(2-methylpropionitrile) (98 mg) and tributyltin hydride (0.95ml) were added to a solution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(740 mg) in benzene (15 ml), and the mixture was refluxed for 20minutes. The reaction mixture was chromatographed on silica gel (15 g)eluting with a mixture of hexane and ethyl acetate (5:1-3:1) to givemethyl 2-[(4R)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate (660mg).

IR(CH₂ Cl₂): 1750, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.97 (s, 3H), 2.20 (s, 3H), 2.3-2.5 (m, 2H), 2.63 (dd,1H, J=3, 16 Hz), 3.11 (dd, 1H, J=5, 16 Hz), 3.77 (s, 3H), 3.7-4.2 (m,1H), 4.8-5.3 (m, 2H), 5.4-6.1 (m, 1H)

EXAMPLE 24 ##STR45##

A solution of benzyl2-[(4S)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (30 mg) inethyl acetate (5 ml) was cooled to -78° C. and ozone was bubbled until ablue color appeared. After stirring for 15 minutes at the sametemperature, the reaction mixture was purged with nitrogen, poured intodilute aqueous sodium bicarbonate and extracted with ethyl acetate. Theextract was washed with water, dried over magnesium sulfate andevaporated to give benzyl[(4S)-4-{(1,2,4-trioxolan-3-yl)methyl}-2-oxoazetidin-1-yl]-glyoxylate(30 mg).

IR (CH₂ Cl₂): 1805, 1750, 1700 cm⁻¹.

EXAMPLE 25 ##STR46##

A stream of ozone was bubbled into a solution of methyl3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]-but-2-enoate (330 mg) inethyl acetate (20 ml) at -78° C. until blue color of ozone appeared. Theexcess of ozone was removed by a stream of nitrogen and the resultantsolution was poured into a solution of sodium bisulfite (1.6 g) andsodium sulfite (0.4 g) in dilute aqueous sodium chloride solution. Themixture was shaken and the organic layer was separated. The aqueouslayer was extracted three times with dichloromethane. The combinedextracts was dried over magnesium sulfate and evaporated to give methyl[(4R)-2-oxo-4-(1,2,4-trioxolan-3-yl-methyl)azetidin-1-yl]glyoxylate (354mg) as an oil.

IR (CH₂ Cl₂): 1810, 1755, 1705 cm⁻¹.

NMR (CDCl₃) δ: 1.9-2.3 (m, 1H), 2.70 (ddd, J=4, 8, 16 Hz, 1H), 3.06(ddd, J=2.5, 4, 18 Hz, 1H), 3.42 (dd, J=6, 18 Hz, 1H), 3.96 (s, 3H),4.2-4.6 (m, 1H), 5.15 (˜t, J=2 Hz, 2H), 5.44 (m, 1H).

EXAMPLE 26 ##STR47##

A solution of methyl[(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (320mg) and dimethyl sulfide (2 ml) in a mixture of dichloromethane (9 ml)and methanol (10 ml) was stirred at 5° C. for 6 hours and at roomtemperature for 15 hours. The mixture was then heated at 50° for 4 hoursand evaporated to give methyl[(4R)-2-oxo-4-(2-oxoethyl)-azetidin-1-yl]glyoxylate.

IR (CH₂ Cl₂): 1810, 1755, 1720 (sh), 1700 cm⁻¹.

EXAMPLE 27 ##STR48##

A solution of methyl[(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (320mg) and dimethyl sulfide (2 ml) in a mixture of methanol (10 ml) anddichloromethane (9 ml) was stirred at 5° C. for six hours, at roomtemperature for 15 hours, and at 55° C. for four hours. The resultantsolution was concentrated and the residue was dissolved in a mixture ofdimethyl sulfide (2 ml) and methanol (15 ml). Silica gel (100 mg) wasadded and the mixture was stirred at room temperature for four days, at50° C. for eight hours, and at 60° C. for seven hours. After evaporationof the solvent, the residue was chromatographed on silica gel (7 g)eluting with 2-5% methanol in dichloromethane to give(4R)-4-(2,2-dimethoxyethyl)-2-oxo-azetidine (57 mg) as an impure oil and(4R)-4-(2-oxoethyl)-2-oxoazetidine (31 mg). Further purification of theimpure oil on silica gel (4 g) eluting with 0.5-2% methanol indichloromethane afforded the pure oil (31 mg) of the former compound.

IR (CH₂ Cl₂): 3400, 1760 cm⁻¹.

NMR (CDCl₃) δ: 1.8-2.0 (m, 2H), 2.62 (ddd, J=1.5, 2.5, 15 Hz, 1H), 3.10(ddd, J=2, 5 15 Hz, 1H), 3.37 (s, 6H), 3.6-3.8 (m, 1H), 4.43 (t, J=5.5Hz, 1H), 6.42 (br s, 1H).

EXAMPLE 28 ##STR49##

A solution of methyl[(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (96mg) and dimethyl sulfide (0.5 ml) in a mixture (1:1) of methanol anddichloromethane (8 ml) was stirred at room temperature for 21 hours andheated at 50° for eight hours. After removal of the solvent, the yellowresidue was chromatographed on silica gel (1.5 g) eluting with 3-5%methanol in dichloromethane to give (4R)-4-(2-oxoethyl)-2-oxoazetidine(20 mg).

IR (CH₂ Cl₂): 3400, 1760, 1720 cm⁻¹.

EXAMPLE 29 ##STR50##

A solution of (4R)-4-(2,2-dimethoxyethyl)-2-oxoazetidine (30 mg) in 80%aqueous acetic acid (1.5 ml) was heated at 62° C. for 2.5 hours under anitrogen atmosphere. After evaporation of the solvent in vacuo, theresidue was chromatographed on silica gel (1.5 g) eluting with 1-3%methanol in dichloromethane to give (4R)-4-(2-oxoethyl)-2-oxoazetidine(5.3 mg).

IR (CH₂ Cl₂): 3400, 1760, 1720 cm⁻¹.

NMR (CDCl₃) δ: 2.63 (dt, J=˜1.5, 16 Hz, 1H), 2.84 (d, J=8 Hz, 1H), 3.20(ddd, J=3, 6, 16 Hz, 1H), 3.44 (d, J=8 Hz, 1H), 4.0 (m, 1H), 6.2 (br s,1H), 9.82 (s, 1H).

EXAMPLE 30 ##STR51##

To a solution of (4R)-4-(2-oxoethyl)-2-oxoazetidine (30 mg) in methanolwas added sodium borohydride (10 mg) at 0° C. The reaction mixture wasstirred at the same temperature for 75 minutes and quenched by additionof acetic acid (three drops). After evaporation of the solvent in vacuo,the residue was chromatographed on silica gel (1.5 g) eluting with1.5-3% methanol in dichloromethane to give(4R)-4-(2-hydroxyethyl)-2-oxoazetidine (20 mg) as a crystalline solid.

IR (CH₂ Cl₂): 3590, 3390, 1755 cm⁻¹.

NMR (CDCl₃) δ: 1.7˜2.0 (m, 2H), 2.62 (ddd, J=1.5, 3, 14 Hz, 1H), 2.96(br s, 1H), 3.11 (ddd, J=2, 5, 14 Hz, 1H), 3.75 (t, J=5.5 Hz, 1H), ˜3.75(m, 1H), 6.76 (br s, 1H).

[α]_(D) ¹²⁶ =+19.6° (CHCl₃, C=0.189).

EXAMPLE 31 ##STR52##

A solution of methyl[(4R)-2-oxo-4-(1,2,4-trioxolan-3-ylmethyl)azetidin-1-yl]glyoxylate (60mg) in methanol (5 ml) was heated at 65°-70° for two hours. Theyellowish solution was cooled to 0° C. and treated with a solution ofdiazomethane (excess) in diethyl ether. After removal of the solvent,the residue was chromatographed on silica gel (1.5 g) eluting with 20%acetone in dichloromethane to give methyl2-[(2R)-4-oxoazetidin-2-yl]acetate (6 mg).

IR (CH₂ Cl₂): 3390, 1760, 1730 cm⁻¹.

NMR (CDCl₃) δ: 2.5-2.8 (m, 3H), 3.16 (ddd, J=2.5, 6, 16 Hz, 1H), 3.74(s, 3H), 3.8-4.1 (m, 1H), 6.3 (m, 1H).

(4R)-4-(2-Oxoethyl)-2-oxoazetidine (5 mg) was afforded from thesubsequent fractions.

EXAMPLE 32 ##STR53##

A mixture of (4R)-4-(2-oxoethyl)-2-oxoazetidine (20 mg) and benzyltriphenylphosporanylidene-acetate (80 mg) in dichloromethane (3 ml) washeated under refluxing for 80 minutes. After removal of the solvent, theresidue was chromatographed on silica gel (2 g) eluting with 3% methanolin dichloromethane to give an oil (30 mg). Further purification on twosilica gel plates (developing solvent: 4% methanol in dichloromethane)afforded crude product (16 mg) of benzyl4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate.

IR (CH₂ Cl₂): 1765, 1720 cm⁻¹.

EXAMPLE 33 ##STR54##

A mixture of benzyl 4-[(2RS)-4-oxoazetidin-2-yl]-but-2-enoate (167 mg),tert-butylhydroperoxide (0.3 ml), and sodium tetrachloropalladate (80mg) in 67% aqueous acetic acid (2.7 ml) was heated at 50° C. for 8.5hours. Additional tert-butylhydroperoxide (0.5 ml) and sodiumtetrachloropalladate (40 mg) were added. The reaction mixture wasstirred at room temperature for three days and heated at 50° C. for 14hours. After evaporation of the solvent in vacuo, the residue was takenup into ethyl acetate (20 ml) and washed with dilute aqueous sodiumchloride. Drying over magnesium sulfate and evaporation left an oil (200mg), which was chromatographed on silica gel plate (developing solvent:20% acetone in dichloromethane) afforded benzyl3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (66 mg).

IR (CH₂ Cl₂): 3400, 1760, 1715 cm⁻¹.

EXAMPLE 34 ##STR55##

A mixture of(4RS)-1-(tert-butyl-dimethylsilyl)-4-(2-oxoethyl)-2-oxoazetidine (240mg) and benzyl triphenylphosphoranylidene-acetate (521 mg) indichloromethane (5 ml) was heated under refluxing for one hour. Afterremoval of the solvent, the residue was chromatographed on silica gel (7g) eluting with a mixture of dichloromethane and acetone (50:1) to givebenzyl4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate(373 mg) as an oil.

IR (CH₂ Cl₂): 1765, 1720 CM⁻¹.

EXAMPLE 35 ##STR56##

To a mixture of benzyl 4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate (16 mg)and triethylamine (18 μl) in dimethylformamide (0.5 ml) was addedtert-butyl-dimethylchlorosilane (15 mg) at 5° C. The mixture was stirredat the same temperature for one hour and at room temperature for 30minutes. The resultant mixture was diluted with ethyl acetate (20 ml),washed with chilled dilute hydrochloric acid, a dilute aqueous sodiumbicarbonate, and brine. Drying over magnesium sulfate and removal of thesolvent left an oil (23 mg), which was chromatographed on a silica gelplate (developing solvent: 5% methanol in dichloromethane) to givebenzyl4-[(2R)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate (13mg).

IR (CH₂ Cl₂): 1730, 1720 (sh) cm⁻¹.

NMR (CDCl₃) δ: 0.21 (s, 3H), 0.23 (s, 3H), 0.93 (s, 9H), 2.1-3.0 (m,2H), 2.60 (dd, J=3, 16 Hz, 1H), 3.14 (dd, J=5, 16 Hz, 1H), 3.4-3.8 (m,1H), 5.16 (s, 2H), 5.90 (dt, J=1, 16 Hz, 1H), 6.90 (dt, J=7, 16 Hz, 1H),7.36 (s, 5H).

EXAMPLE 36 ##STR57##

To a solution of benzyl4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate(45 mg) in methanol was added 1N hydrochloric acid (0.1 ml) at 0°. Afterstirring at room temperature for 2.5 hours, the reaction mixture wasneutrallized to pH 7 with saturated aqueous sodium bicarbonate. Theresultant solution was concentrated, taken up into ethyl acetate (15ml), and washed in turn with water and brine. Drying over magnesiumsulfate and removal of the solvent left an oil, which waschromatographed on a silica gel plate (developing solvent: 6% methanolin dichloromethane) to give benzyl4-[(2RS)-4-oxoazetidin-2-yl]but-2-enoate (30 mg) as a crystalline solid.

IR (CH₂ Cl₂): 3390, 1765, 1715, 1655 cm⁻¹.

NMR (CDCl₃) δ: 2.40-2.80 (m, 3H), 3.10 (ddd, J=3,5,15 Hz, 1H), 3.6-3.9(m, 1H), 5.18 (s, 2H), 5.93 (br d, J=16 Hz, 1H), 6.50 (br s, 1H), 6.92(dt, J=7, 16 Hz, 1H), 7.36 (s, 5H).

EXAMPLE 37 ##STR58##

To a solution of benzyl4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]but-2-enoate(50 mg) in 60% aqueous acetic acid (1.5 ml) were addedtert-butyl-hydroperoxide (40 μl) and sodium tetrachloropalladate (18mg). The solution was heated at 55° C. for 5.5 hours. Additionaltert-butyl-hydroperoxide (100 μl) and sodium tetrachloropalladate (18mg) were added and stirring at 50° C. was continued for further 11hours. After evaporation of the solvent in vacuo, the residue was takenup into ethyl acetate and washed in turn with water (twice) and brine.Drying over magnesium sulfate and removal of the solvent left an oil (30mg) which was chromatographed on a silica gel plate (developing solvent:25% acetone in benzene) afforded benzyl3-oxo-4-[(2RS)-4-oxoazetidin-2-yl]butanoate (13 mg).

IR (CH₂ Cl₂): 3400, 1760, 1715 cm⁻¹.

NMR (CDCl₃) δ: 2.54 (ddd, J=1, 3, 15 Hz, 1H), 2.9 (m, 2H), 3.15 (ddd,J=3, 6, 15 Hz, 1H), 3.51 (s, 2H), 3.9 (m, 1H), 5.17 (s, 2H), 6.1 (m,1H), 7.37 (s, 5H).

Benzyl4-[(2RS)-1-(tert-butyl-dimethylsilyl)-4-oxoazetidin-2-yl]-3-oxobutanoate(3.5 mg) was afforded from the subsequent fractions.

IR (CH₂ Cl₂): 1755, 1735 (sh), 1715 cm⁻¹.

EXAMPLE 38 ##STR59##

A solution of methyl2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (85 mg) inethyl acetate (7 ml) was cooled to -78° C. and ozone was bubbled until ablue color appeared. After stirring for 10 minutes at the sametemperature, the reaction mixture was purged with nitrogen.

To this solution was added sodium borohydride (60 mg) and the mixturewas stirred for 30 minutes at -78° C. Acetic acid (0.12 ml) was thenadded and the mixture was stirred for 2 hours during which time thetemperature was gradually raised to 0° C. The reaction mixture wasdiluted with ethyl acetate (10 ml), washed successively with water,dilute aqueous sodium bicarbonate and brine. Drying over magnesiumsulfate and evaporation gave an oil (20 mg), which was chromatographedon silica gel (1 g) eluting with a mixture of methylene chloride andmethanol (10:1) to give methyl2-hydroxy-2-[(4R)-4-(2-hydroxyethyl)-2-oxoazetidin-1-yl]acetate (12 mg).

IR (CH₂ Cl₂): 3500, 1765, 1745 (sh) cm⁻¹.

EXAMPLE 39 ##STR60##

A stream of ozone was bubbled into a solution of methyl2-[(3R,4R)-4-{2-(methoxycarbonylmethyl)allyl}-2-oxo-3-phthalimidoazetidin-1-yl]-3-methyl-but-2-enoate(180 mg) in ethyl acetate (10 ml) at -78° C. until blue color of ozoneappeared. After stirring for 2 minutes at the same temperature, theexcess of ozone was removed by a stream of nitrogen. The resultantsolution was poured into a chilled dilute aqueous sodium bisulfate andextracted with ethyl acetate (10 ml). The extract was washed twice withbrine, dried over magnesium sulfate, and evaporated to afford methyl4-[(2R,3R)-1-methoxalyl-4-oxo-3-phthalimidoazetidin-2-yl]-3-oxobutanoate(179 mg) as an oil. This material could be crystallized from 7%dichloromethane in methanol, mp 130°-132° C.

IR (nujol): 1800, 1780, 1760, 1735 (sh), 1730 (sh), 1720 cm⁻¹.

NMR (CDCl₃) δ: 3.20 (dd, J=8, 19 Hz, 1H), 3.56 (s, 2H), 3.78 (s, 3H),3.80 (dd, J=4, 19 Hz, 1H), 4.00 (s, 3H), 4.84 (dt, J=4, 8 Hz, 1H), 5.34(d, J=4 Hz, 1H), 7.7-8.0 (m, 4H).

EXAMPLE 40 ##STR61##

A solution of methyl4-[(2R,3R)-1-methoxalyl-4-oxo-3-phthalimidoazetidin-2-yl]-3-oxobutanoate(68 mg) in methanol (4 ml) was stirred at room temperature for 16 hoursand heated at 55°-60° C. for two hours. The resultant solution wasevaporated, and the residue was chromatographed on a silica gel plate(developing solvent: 20% acetone in dichloromethane) to afford methyl3-oxo-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]butanoate (35 mg) asan amorphous solid. Crystallization from a mixture of ethyl acetate andether gave crystals (26 mg), mp 120°-124° C.

IR (CH₂ Cl₂): 1785, 1770 (sh), 1740 (sh), 1720 cm⁻¹.

NMR (CDCl₃) δ: 3.15 (d, J=6.5 Hz, 1H), 3.52 (s, 2H), 3.73 (s, 3H), 4.40(dt, J=3, 6.5 Hz, 1H), 5.05 (d, J=3 H, 1H), 6.78 (brs, 1H), 7.6-8.1 (m,4H).

EXAMPLE 41 ##STR62##

A mixture of methyl3-oxo-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]butanoate (300 mg),pyridinium p-toluenesulfonate (25 mg), p-toluene-sulfonic acidmonohydrate (20 mg), and trimethyl orthoformate (0.6 ml) in a mixture ofmethanol (3 ml) and dichloromethane (1 ml) was heated to reflux for sixhours. Additional trimethyl orthoformate (0.2 ml) was added and thereflux was continued for one hour. After the solution was cooled to roomtemperature, pyridine (three drops) was added. The resultant solutionwas evaporated and the residue was dissolved in ethyl acetate (20 ml).The solution was washed in turn with dilute hydrochloric acid, water,and brine, dried over magnesium sulfate and evaporated. The residue waschromatographed on silica gel (8 g) eluting with 5-10% acetone indichloromethane to give an (E,Z)-isomeric mixture of methyl3-methoxy-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]but-2-enoate (213mg) as a crystalline solid, mp 208°-220° C.

IR (CH₂ Cl₂): 3400, 1780, 1770 (sh), 1720, 1630 cm⁻¹.

NMR (DMSO-d₆) δ: 3.1-3.4 (m, 2H), 3.55 and 3.57 (a pair of singlet, 3H),3.60 (s, 3H), 4.10 (dt, J=2, 7 Hz, 1H), 5.03 (d, J=2 Hz, 1H), 5.13 (s,1H), 7.88 (s, 4H), 8.45 and 8.58 (a pair of broad singlet, a ratio of1:4, 1H).

EXAMPLE 42 ##STR63##

A stream of ozone was bubbled into a solution of methyl2-[(3R,4R)-4-{2-(methoxycarbonylmethyl)allyl}-2-oxo-3-phthalimidoazetidin-1-yl]-3-methyl-but-2-enoate(4.55 g) in ethyl acetate (80 ml) at -78° C. until blue color of ozoneappeared. After the excess of ozone was removed by a stream of nitrogen,the resultant solution was allowed to warm to 0° C. and washedsuccessively with an aqueous sodium bisulfite (10 g) and sodium sulfite(3.5 g), a dilute aqueous sodium chloride, and a saturated aqueoussodium chloride. Drying over magnesium sulfate and evaporation affordedmethyl4-[(2R,3R)-1-methoxalyl-4-oxo-3-phthalimidoazetidin-2-yl]-3-oxo-butanoateas an amorphous solid. This material was suspended in a mixture ofmethanol (80 ml) and dichloromethane (10 ml), and heated at 60° C. foreight hours. The resultant solution was evaporated and the residue waschromatographed on silica gel (60 g) eluting with 10-25% acetone indichloromethane to give an amorphous solid (2.405 g). Crystallizationfrom a mixture of ethyl acetate and diethyl ether afforded methyl3-oxo-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]-butanoate (2.08 g),mp 116°-120° C.

EXAMPLE 43 ##STR64##

To a mixture of methyl3-methoxy-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]but-2-enoate[(E,Z)-isomericmixture] (186 mg) and triethylamine (90 μl) in dimethylformamide (2 ml)was added tert-butyldimethyl-chlorosilane (96 mg) at 0° C. After themixture was stirred at 0° C. for 30 minutes and at room temperature forone hour, additional tert-butyl-dimethyl-chlorosilane (32 mg) andtriethylamine (30 μl) were added. The mixture was stirred at 0° C. for30 minutes and at room temperature for 1.5 hours, diluted with ethylacetate (20 ml), and washed with water (twice), a dilute aqueous sodiumbicarbonate solution, and brine. Drying over magnesium sulfate andremoval of the solvent afford on oil (280 mg) which was chromatographedon silica gel (6 g) eluting with 10% acetone in benzene to give methyl4-[(2R,3R)-1-(tert-butyl-dimethylsilyl-4-oxo-3-phthalimidoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](209 mg) as an amorphous solid.

IR (CH₂ Cl₂): 1780 (sh), 1750, 1720, 1625 cm⁻¹.

NMR (CDCl₃) δ: 0.30 (s, 6H), 0.99 (s, 9H), 2.4-3.2 (m, 2H), 3.46 (s,3H), 3.62 (s, 3H), 4.1-4.6 (m, 1H) 4.97 (s, 1H), 5.19 (d, J=2.5 Hz, 1H),7.72 (m, 4H).

EXAMPLE 44 ##STR65##

A mixture of methyl4-[(2R,3R)-1-(tert-butyl-dimethylsilyl)-4-oxo-3-phthalimidoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](182 mg) and N,N-dimethyl-1,3-propanediamine (126 μl) in amixture of methanol (1 ml) and dichloromethane (1 ml) was left at roomtemperature for four days. After evaporation of the solvent, the residuewas chromatographed on silica gel (2.5 g) eluting with 3-5% methanol indichloromethane to give an oil (36 mg). Further purification on a silicagel plate (developing solvent: 15% methanol in dichloromethane) affordedmethyl4-[(2R,3R)-3-amino-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](35 mg) as an oil.

IR (CH₂ Cl₂): 3390, 1765, 1710, 1630 cm⁻¹.

NMR (CDCl₃) δ: 1.82 (brs, 2H), 2.8-3.9 (m, 3H), 3.70 (s, 6H), 3.95 (brs,1H), 5.15 (s, 1H), 6.45 (brs, 1H).

EXAMPLE 45 ##STR66##

A solution of methyl4-[(2R,3R)-3-amino-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](145 mg) in acetic formic anhydride (1 ml) was stirred at 5° C.for one hour. The resultant solution was evaporated in vacuo, and theresidue was chromatographed on silica gel (2.5 g) eluting with 3 to 5%methanol in dichloromethane to give methyl4-[(2R,3R)-3-formamido-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](133 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3400, 1770, 1700, 1625 cm⁻¹.

NMR (CDCl₃) δ: 2.9-3.3 (m, 2H), 3.66 (s, 3H), 3.68 (s, 3H), 3.9 (m, 1H),4.75 (dd, J=2, 8 Hz, 1H), 5.10 (s, 1H), 7.00 (brs, 1H), 7.48 (brd, J=8Hz, 1H), 8.15 (s, 1H).

EXAMPLE 46 ##STR67##

To a solution of methyl4-[(2R,3R)-3-formamido-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](133 mg) and 2,6-lutidine (0.96 ml) in dichloromethane (3 ml)was added phosphorus oxychloride (0.15 ml) at 0°. After stirring at thesame temperature for four hours, the reaction mixture was diluted withethyl acetate (20 ml), and washed with a dilute aqueous sodium chloride,dilute phosphoric acid, a dilute aqueous sodium chloride, ice-water, anda saturated aqueous solution of sodium chloride in turn. Drying overmagnesium sulfate and removal of the solvent gave a brown oil, which waschromatographed on silica gel (2 g) eluting with 3% methanol indichloromethane to give methyl4-[(2R,3R)-3-isocyano-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](70 mg) as a crystalline solid

IR (CH₂ Cl₂): 3380, 2200, 1795, 1705, 1630 cm⁻¹.

NMR (CDCl₃) δ: 3.1-3.4 (m, 2H), 3.68 (s, 6H), 4.06 (dt. J=2.5, 6 Hz,1H), 4.60 (m, 1H), 5.23 (s, 1H), 6.52 (brs, 1H).

EXAMPLE 47 ##STR68##

A mixture of methyl4-[(2R,3R)-3-isocyano-4-oxoazetidin-2-yl]-3-methoxybut-2-enoate[(E,Z)-isomericmixture](50 mg), tri-n-butyltin hydride (90 μl), and2,2'-azobis-(2-methylpropionitrile) (5 mg) in benzene (5 ml) was heatedto reflux for one hour under a nitrogen atmosphere. The reaction mixturewas cooled to room temperature and chromatographed on silica gel (2.5 g)eluting first with dichloromethane and then 4% methanol indichloromethane to give methyl3-methoxy-4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate[(E,Z)-isomericmixture](35 mg) as a crystalline solid.

IR (CH₂ Cl₂): 3390, 1760, 1710, 1625 cm⁻¹.

NMR (CDCl₃) δ: 2.6-2.9 (m, 1H), ˜3.0 (m, 2H), 3.30 (dd, J=6, 14 Hz, 1H),3.66 (s, 3H), 3.68 (s, 3H), 3.85 (m, 1H), 5.11 (s, 1H), 6.28 (brs, 1H).

Mass spectrum: m/e 199 (M⁺), 171, 157, 156, 126, 70.

EXAMPLE 48 ##STR69##

A solution of methyl3-methoxy-4-[(2R)-4-oxoazetidin-2-yl]but-2-enoate[(E,Z)-isomericmixture](35 mg) in 1N hydrochloric acid (2 ml) was stirred at 25° C. fortwo hours. The resultant solution was saturated with sodium chloride andextracted three times with chloroform. The combined extracts were driedover magnesium sulfate and evaporated. The residue (29 mg) waschromatographed on silica gel (1.5 g) eluting with 2% methanol indichloromethane to give methyl3-oxo-4-[(2R)-4-oxoazetidin-2-yl]butanoate (28 mg), mp. 45.0°-46.5° C.:

IR (CH₂ Cl₂): 3400, 1760 (br), 1715 cm⁻¹.

NMR (CDCl₃) δ: 2.4-3.3 (m, 4H), 3.50 (s, 2H), 3.76 (s, 3H), 4.9 (m, 1H),6.40 (brs, 1H).

Mass spectrum: m/e 185 (m⁺), 157, 142, 116, 112, 101, 70, 59, and 43.

[α]_(D) ²⁶ : +61.3° (chloroform, c=0.261).

EXAMPLE 49 ##STR70##

A stream of ozone was bubbled into a solution of methyl3-methyl-2-[(3R,4R)-2-oxo-3-phthalimido-4-allylazetidin-1-yl]but-2-enoate(5.00 g) in a mixture of ethyl acetate (60 ml) and dichloromethane (30ml) at -78° until blue color of ozone appeared. After five minutes, theexcess of ozone was removed by a stream of nitrogen. The resultantcolorless solution was allowed to warm to -20° C., diluted with ethylacetate (90 ml) and then washed in turn with an aqueous containingsodium bisulfite (6.0 g) and sodium sulfite (2.5 g), and brine. Dryingover magnesium sulfate and evaporation gave an amorphous solid (4.90 g).This material was dissolved in a mixture of methanol (50 ml) anddichloromethane (5 ml), and dimethyl sulfide (4 ml) was added. Thesolution was stirred overnight at room temperature and heated at 50° forseven hours. After evaporation of the solvent, the residue waschromatographed on silica gel (20 g) eluting with 20-33% acetone indichloromethane to afford an impure material (4 g). Crystallization fromethyl acetate afforded a mixture (1.52 g) of(3R,4R)-2-oxo-4-(2-oxoethyl)-3-phthalimidoazetidine and itsmethanol-hemiacetal.

IR (Nujol): 3280 (br), 1770 (sh), 1750, 1705 cm⁻¹.

NMR (DMSO-d₆) δ: 1.7-2.1 (m, ˜1H), 2.9-3.5 (m, ˜4H), 3.8-4.7 (m, ˜1.5H),5.0 (m, 1H), 6.10 (dd, J=2 and 7 Hz, ˜0.5H), 7.95 (s, 4H), 8.47 and 8.55(a pair of broad singlet, 1H), 9.70 (s, ˜0.5H).

EXAMPLE 50 ##STR71##

A stream of ozone was bubbled into a solution of methyl3-methyl-2-[(3R,4R)-2-oxo-3-phthalimido-4-allylazetidin-1-yl]but-2-enoate(250 mg) in a mixture of ethyl acetate (5 ml) and dichloromethane (2 ml)at -78° C. until blue color of ozone appeared. After five minutes, theexcess of ozone was removed by a stream of nitrogen at the sametemperature. Dimethyl sulfide (0.5 ml) was added. The resultant yellowsolution was allowed to warm to -10° C. and kept for one hour at thesame temperature. Methanol (2 ml) was added and the solution was stirredat 0° C. for three hours and at room temperature overnight. Afterconcentration of the reaction mixture, the residue was taken up intoethyl acetate and washed with a dilute aqueous sodium bisulfate, water,and brine. Drying over magnesium sulfate and removal of the solvent gavean oil (230 mg) which was dissolved in methanol (8 ml). Dimethyl sulfide(0.5 ml) was added thereto. After heating at 55° C. for three hours andat 65° for two hours, the solution was evaporated. The residue waschromatographed on silica gel (2 g) eluting with 5-17% acetone indichloromethane to afford(3R,4R)-4-(2,2-dimethoxyethyl)-3-phthalimido-2-oxoazetidine (126 mg) asan amorphous solid.

IR (CH₂ Cl₂): 3410, 1785, 1770 (sh), 1725 cm⁻¹.

NMR (CDCl₃) δ: ˜2.1 (m, 2H), 3.36 (s, 6H), 4.20 (dt, J=3, 7 Hz, 1H),4.51 (t, J=5 Hz, 1H), 5.07 (d, J=3 Hz, 1H), 6.55 (brs, 1H), 6.5-7.1 (m,4H).

EXAMPLE 51 ##STR72##

A solution of(3R,4R)-4-(2,2-dimethoxyethyl)-3-phthalimido-2-oxoazetidine (65 mg) in80% aqueous acetic acid (1.5 ml) was heated at 64° for two hours. Afterevaporation of the solvent in vacuo, the residue was crystallized from amixture of diethyl ether and ethyl acetate to afford(3R,4R)-4-(2-oxoethyl)-3-phthalimido-2-oxoazetidine (42 mg).

IR (CH₂ Cl₂): 3400, 1785, 1770, 1720 cm⁻¹.

EXAMPLE 52 ##STR73##

A mixture of (3R,4R)-4-(2-oxoethyl)-3-phthalimido-2-oxoazetidine (amixture of the free aldehyde and its methanol-hemiacetal) (1.52 g) andbenzyl triphenylphosphoranylideneacetate (3.15 g) in dichloromethane (30ml) was heated under refluxing for 75 minutes in a nitrogen atmosphere.After removal of the solvent, the residue was chromatographed on silicagel (60 g) eluting with 5-10% acetone in dichloromethane to give an oil(1.69 g). Crystallization from diethyl ether afforded benzyl4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]but-2-enoate (1.53 g), mp115°-120° C.

IR (Nujol): 3280, 1775 (sh), 1765, 1730, 1710 cm⁻¹.

NMR (CDCl₃) δ: 2.66 (t, J=7 Hz, 2H), 4.17 (dt, J=2.5, 7 Hz, 1H), 5.03(d, J=2.5 Hz, 1H), 5.15 (s, 2H), 6.00 (d, J=16 Hz, 1H), 6.72 (brs, 1H),6.97 (dt, J=7, 16 Hz, 1H), 7.35 (s, 5H), 7.8 (m, 4H).

EXAMPLE 53 ##STR74##

A mixture of benzyl4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]but-2-enoate (35 mg),tert-butylhydroperoxide (20 μl) and sodium tetrachloropalladate (6 mg)in 60% aqueous acetic acid (1 ml) was stirred at room temperature forone hour and then heated at 50° for ten hours, during which timeadditional sodium tetrachloropalladate (15 mg) andtert-butylhydroperoxide (80 μl) in two portions were added. Theresultant solution was evaporated in vacuo. The residue was taken upinto ethyl acetate and washed with water and brine. Drying overmagnesium sulfate and removal of the solvent gave an oil (40 ml), whichwas chromatographed on two silica gel plates [developing solvent: amixture of benzene and acetone (5:2)] to give benzyl3-oxo-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]butanoate (15 mg) asan oil.

IR (CH₂ Cl₂): 3400, 1785, 1770 (sh), 1720 cm⁻¹.

NMR (CDCl₃)δ: 3.04 (˜d, J=6 Hz, 2H), 3.51 (s, 2H), 4.35 (m, 1H), 4.97(d, J=3 Hz, 1H), 5.16 (s, 3H), 6.42 (brs, 1H), 7.34 (s, 5H), 7.80 (m,4H).

EXAMPLE 54 ##STR75##

A mixture of benzyl4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]but-2-enoate (960 mg) andN,N-dimethyl-1,3-propanediamine (0.84 ml) in tetrahydrofuran (8 ml) wasstirred at room temperature for four days. After evaporation of thesolvent, the residue was chromatographed on silica gel (20 g) elutingwith 25-50% acetone in benzene to give an oil (250 mg). Furtherpurification on silica gel (8 g) eluting with 3-5% methanol indichloromethane afforded benzyl4-[(2R,3R)-3-amino-4-oxoazetidin-2-yl]but-2-enoate (146 mg) as an oil.

IR (CH₂ Cl₂): 3390, 1770, 1720, 1655 cm⁻¹.

NMR (CDCl₃) δ: 1.80 (s, 2H), 2.4-2.8 (m, 2H), 3.49 (ddd, J=2.5, 6 Hz,1H), 3.80 (d, J=2 Hz, 1H), 5.20 (s, 2H), 6.00 (dt, J=1.5, 16 Hz, 1H),6.45 (brs, 1H), 7.00 (dt, J=7, 16 Hz, 1H), 7.38 (s, 5H).

EXAMPLE 55 ##STR76##

A stream of ozone was bubbled into a solution of methyl2-[(3S,4R)-4-[2-(methoxycarbonylmethyl)allyl]-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(190 mg) in ethyl acetate (14 ml) at -78° C. until blue color appeared.After stirring at -78° C. for two minutes, the excess of ozone wasremoved by a stream of nitrogen. The solution was diluted with ethylacetate, and washed with a chilled aqueous sodium bisulfite (1.0 g) andbrine. Drying over magnesium sulfate and removal of the solvent gave anoil (182 mg). The residue was dissolved in dichloromethane (2.5 ml) andcooled to 0° C. To this solution were added methanol (7.5 ml) anddimethyl sulfide (0.7 ml) and the resultant solution was stirred at 0°for 25 hours. The mixture was then heated to 50° C. for 22 hours andallowed to stand at room temperature for four days. After removal of thesolvent, the residue was chromatographed on silica gel (6 g) elutingwith 5-20% acetone in dichloromethane to give methyl4-[(2R,3S)-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]-3-oxobutanoate(122 mg).

IR (CH₂ Cl₂): 3380, 1765, 1750, 1715, 1520, 1350 cm⁻¹.

NMR (CDCl₃)δ: 1.46 (d, J=6.5 Hz, 3H), 2.90-3.05 (m, 2H), 3.10 (dd,J=2.2, 4.5 Hz, 1H), 3.48 (s, 2H), 3.73 (s, 3H), 3.8 (m, 1H), 5.13 (dq,J=4.5, 6.5 Hz, 1H), 5.24 (s, 2H), 6.51 (br s, 1H), 7.53 (d, J=9 Hz, 2H)and 8.18 (d, J=9 Hz, 2H).

EXAMPLE 56 ##STR77##

Methyl4-[(2R,3S)-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(61 mg) was afforded from methyl2-[(3S,4R)-4-{2-(methoxycarbonylmethyl)allyl}-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(90 mg) in a similar manner to that of Example 55.

IR (CH₂ Cl₂): 3380, 1765, 1745, 1715, 1520, 1350 cm⁻¹.

NMR (acetone-d₆) δ: 1.42 (d, J=6.5 Hz, 2H), 1.46 (d, J=6.5 Hz, 1H),3.0-3.2 (m, 3H), 3.59 (s, 2H), 3.69 (s, 3H), 3.80 (dt, J=2.5, 7 Hz,1/3H), 3.95 (ddd, J=2.5, 6, 8 Hz, 2/3H), 5.10 (quintet, J=6.5 Hz, 2/3H),5.15 (m, 1/3H, hidden), 7.15 (brs, 1/3H), 7.23 (brs, 2/3H), 7.66 (d, J=9Hz, 2H), 8.23 (d, J=9 Hz, 2H).

EXAMPLE 57 ##STR78##

A mixture of methyl2-[(3S,4R)-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(62 mg) in ethyl acetate (5 ml) was cooled to -70° C. and ozone wasbubbled until a blue color appeared. After stirring for 15 minutes atthe same temperature, the reaction mixture was purged with nitrogen andpoured into a mixture of ethyl acetate and an aqueous sodium bisulfiteand sodium sulfite (4:1). The organic layer was separated and washedwith brine. Drying over magnesium sulfate and evaporation gave an oil(56 mg) ofmethyl[(3S,4R)-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-4-(1,2,4-tri-oxolan-3-ylmethyl)-2-oxoazetidin-1-yl]glyoxylate.This oil was dissolved in a mixture of methanol (4 ml) and methylenechloride (2 ml), and dimethyl sulfide (0.5 ml) was added at 0° C. Themixture was stirred at the same temperature for two hours and at roomtemperature overnight. After further stirring at 50° C. for 3 hours, themixture was evaporated. The residue was again dissolved in methanol (14ml), and dimethyl sulfide (0.5 ml) was added thereto. The mixture wasstirred at room temperature overnight and then evaporated. The residuewas purified by preparative thin layer chromatography (silica gel)developing with benzene and acetone (1:1) to give a mixture (5 mg) of(3S,4R)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)-2-oxoazetidine[IR(CH₂ Cl₂): 3375, 1770, 1750, 1720 cm⁻¹ ] and its dimethyl acetal [IR(CH₂ Cl₂): 1760, 1750 cm⁻¹.

NMR (CDCl₃) δ: 1.45 (d, 3H, 6.5 Hz), 1.94 (dd, 2H, J=6, 5.5 Hz), 3.0-3.2(m, 1H), 3.32 (s, 3H), 3.5-3.8 (m, 1H), 4.41 (t, 1H, J=5.5 Hz), 4.9-5.3(m, 1H), 5.24 (s, 2H), 6.12 (broad s, 1H), 7.84 (A₂ B₂, 4H, J=9 Hz).].

EXAMPLE 58 ##STR79##

A solution of methyl3-methyl-2-[(3S,4R)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-4-allylazetidin-1-yl]but-2-enoate(135 mg) in ethyl acetate (10 ml) was cooled to -70° C. and ozone wasbubbled until a blue color appeared. After stirring for 15 minutes atthe same temperature, the mixture was purged with nitrogen and pouredinto a mixture of ethyl acetate and an aqueous sodium bisulfite andsodium sulfite (3:1). The organic layer was separated and washed withbrine, dried over magnesium sulfate and evaporated to givemethyl[(3S,4R)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxo-4-(1,2,4-tri-oxolan-3-ylmethyl)]glyoxylate.The product was dissolved in methanol (4 ml) and dimethyl sulfide (1 ml)was added at 0° C. The mixture was stirred at the same temperature for 2hours and at room temperature for 2 hours. Additional 0.5 ml of dimethylsulfide was added and the mixture was stirred at 50° C. for 6 hours.After standing overnight at room temperature, the mixture was evaporatedand the residue was dissolved in benzene. The solution was evaporatedand the residue was chromatographed on silica gel (3 g) eluting withhexane and ethyl acetate (4:1-1:2) to give(3S,4R)-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)-2-oxoazetidine(15 mg).

[IR (CH₂ Cl₂): 3375, 1770, 1750, 1720 cm⁻¹ ] and its dimethyl acetal (37mg).

IR (CH₂ Cl₂): 1760, 1750 cm⁻¹.

NMR (CDCl₃) δ: 1.45 (d, 3H, J=6.5 Hz), 1.94 (dd, 2H, J=6, 5.5 Hz), 3.10(dd, 1H, J=5, 2.5 Hz), 3.32 (s, 3H), 3.62 (dt, 1H, J=2.5, 6 Hz), 4.41(t, 1H, J=5.5 Hz), 4.9-5.3 (m, 1H), 5.24 (s, 2H), 6.28 (broad s, 1H),7.84 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 59 ##STR80##

A mixture of(3S,4R)-4-(2,2-dimethoxyethyl)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidine(12 mg) in 80% aqueous acetic acid (1 ml) was stirred at 50° C. for 4hours. After standing at -20° C. overnight, the mixture was evaporatedand the residue was dissolved in ethyl acetate. The solution was washedwith aqueous sodium bicarbonate and brine, dried over magnesium sulfateand evaporated to give(3S,4R)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(2-oxoethyl)]azetidine(8 mg).

IR (CH₂ Cl₂): 3420, 1770, 1750, 1720 cm⁻¹.

EXAMPLE 60 ##STR81##

(3S,4R)-3[(1S)-1-(P-Nitrobenzyloxycarbonyloxy)-ethyl]-2-oxo-4-(2-oxoethyl)azetidinewas prepared from(3S,4R)-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-(2,2-dimethoxyethyl)-2-oxoazetidinein a similar manner to that of Example 59.

IR (CH₂ Cl₂): 3375, 1770, 1750, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.48 (d, 3H, J=7 Hz), 2.92 (d, 2H, J=6 Hz), 3.12 (dd, 1H,J=5, 2.5 Hz), 3.86 (dt, 1H, J=2.5, 6 Hz), 5.0-5.3 (m, 1H), 5.25 (s, 2H),6.48 (s, 1H), 7.84 (A₂ B₂, 4H, J=9 Hz), 9.74 (s, 1H).

EXAMPLE 61 ##STR82##

(3S,4R)-3-[(1RS)-1-(p-Nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(2-oxoethyl)azetidine(8 mg) was dissolved in methanol (0.8 ml) and sodium borohydride (2 mg)was added at 0° C. The mixture was then stirred for 30 minutes at thesame temperature and acetic acid (3 drops) was added. The mixture wasevaporated and the residue was dissolved in ethyl acetate, washed withaqueous sodium bicarbonate, and brine, dried over magnesium sulfate andevaporated. The residue was purified by preparative thin layerchromatography (silica gel) developing with benzene: acetone (1:1) togive(3S,4R)-4-(2-hydroxyethyl)-3-[(1RS)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-2-oxoazetidine(5 mg).

IR (CH₂ Cl₂): 3560, 3370, 1760, 1750 cm⁻¹.

NMR (CDCl₃) δ: 1.47 (d, 3H, J=7 Hz), 1.88 (q, 2H, J=6 Hz), 3.06 and 3.14(dd, J=7.5, 2.5 Hz, dd, J=5, 2.5 Hz, 1H (1:3)), 3.5-4.0 (m, 3H), 5.0-5.4(m, 1H), 5.24 (s, 2H), 6.25 (br s, 1H), 7.90 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 62 ##STR83##

(3S,4R)-4-(2-hydroxyethyl)-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidinewas prepared from(3S,4R)-4-(2-oxoethyl)-3-[(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidinein a similar manner to that of Example 61.

IR (CH₂ Cl₂): 3560, 3370, 1760, 1750 cm⁻¹.

NMR (CDCl₃) δ: 1.44 (d, 3H, 7 Hz), 1.86 (q, 2H, 6 Hz), 2.12 (broad s,1H), 3.16 (dd, 1H, J=5, 2.5 Hz), 3.66 (dt, 1H, J=2.5, 6 Hz), 3.76 (t,2H, J=6 Hz), 5.12 (dq, 1H, J=5, 7 Hz), 5.24 (s, 2H), 6.46 (s, 1H), 7.90(A₂ B₂, 4H, J=9 Hz).

EXAMPLE 63 ##STR84##

To a solution of methyl2-[(3S,4S)-4-chloro-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(200 mg) and p-nitrobenzyl 3-(trimethylsilylmethyl)but-3-enoate (320 mg)in dichloromethane (1.7 ml) was added silver tetrafluoroborate (133 mg)all at once at -78° C. The stirring mixture was gradually allowed towarm to 0° C. during 45 minutes period and kept at the same temperaturefor 40 minutes. The mixture was diluted with ethyl acetate (5 ml). Asaturated aqueous sodium chloride (2 ml) was added and the mixture wasbrought to pH 7 with a saturated aqueous sodium bicarbonate. Afterfurther dilution with ethyl acetate (15 ml), the mixture was filteredthrough Celite. The organic layer was separated, washed with brine,dried over magnesium sulfate and evaporated to leave an oil, which waschromatographed on silica gel (8 g) eluting with 1 to 5% acetone indichloromethane to give an oil (215 mg). Further purification by asilica gel column chromatography (8 g) eluting with 10 to 40% ethylacetate in hexane afforded methyl3-methyl-2-[(3S,4R)-4-{2-(p-nitrobenzyloxycarbonylmethyl)allyl}3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate(200 mg.).

IR (CH₂ Cl₂): 1750, 1725 (sh), 1605, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.50 (d, J=6.5 Hz, 1H), 1.94 (s, 3H), 2.20 (s, 3H), 2.48(AB part of ABX system, 8 lines, J=6,8, 14 Hz, 2H), 3.15 (s, 2H), 3.19(dd, J=2.5, 5 Hz, 1H), 3.75 (3H, s), 4.12 (ddd, J=2.5, 6, 8 Hz, 1H),5.02 (s, 2H), 5.20 (m, hidden, 1H), 5.23 (s, 2H), 5.28 (s, 2H), 7.52 (d,J=9 Hz, 2H), 7.56 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 4H).

EXAMPLE 64 ##STR85##

To a solution of a mixture (55:45) of methyl2-[(3S,4RS)-4-chloro-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(392 mg) and p-nitrobenzyl 3-(trimethylsilylmethyl)-but-3-enoate (562mg) in dichloromethane (3.5 ml) was added silver tetrafluoroborate (260mg) all at once at -78° C. under a nitrogen atmosphere. The stirringmixture was gradually allowed to warm to 0° C. during 45 minutes periodand kept at the same temperature for one hour. The mixture was dilutedwith ethyl acetate (10 ml). A saturated aqueous sodium chloride (3 ml)was added, and the mixture was neutralized to pH 7 with a saturatedaqueous sodium bicarbonate. The resultant mixture was filtered throughCelite. After further dilution with ethyl acetate (20 ml), the organiclayer was separated and washed with brine. Drying over magnesium sulfateand evaporation left an oil, which was chromatographed on silica gel (15g) eluting with 1-5% acetone in dichloromethane to give an oil (326 mg).Further purification by a silica gel column chromatography (15 g)eluting with 10-40% ethyl acetate in hexane afforded of methyl3-methyl-2-[(3S,4R)-4-{2-(p-nitrobenzyloxycarbonylmethyl)allyl}-3-{(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate(289 mg).

IR (CH₂ Cl₂): 1750, 1720 (sh), 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.46 (d, J=6.5 Hz, 3H), 1.95 (s, 3H), 2.19 (s, 3H), 2.50(m, 2H), 3.06 (dd, J=2.5, 7 Hz, 1H), 3.13 (s, 2H), 3.74 (s, 3H), 4.10(ddd, J=2.5, 6, 7.5 Hz, 1H), 5.01 (s, 2H), 5.17 (quintet, partiallyhidden, J=7 Hz, 1H), 5.20 (s, 2H), 5.25 (s, 2H), 7.48 (d, J=9 Hz, 2H),7.52 (d, J=9 Hz, 2H), 8.18(d, J=9 Hz, 4H).

[α]_(D) ²² :-5.65 (c=0.513, CHCl₃).

EXAMPLE 65 ##STR86##

Ozone was bubbled into a solution of methyl3-methyl-2-[(3S,4R)-4-{2-(p-nitrobenzyloxycarbonylmethyl)-allyl}-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate(187 mg) in ethyl acetate (8 ml) at -78° C. until blue color appeared.After three minutes, the excess of ozone was removed by a stream ofnitrogen. The solution was diluted with ethyl acetate (20 ml) and washedwith a chilled aqueous sodium bisulfite (1 g), a dilute aqueous sodiumchloride, and a saturated aqueous sodium chloride. The organic layer wasdried over magnesium sulfate and evaporated to give an amorphous solid(191 mg). This residue was dissolved in dichloromethane (2.5 ml)containing dimethyl sulfide (0.7 ml) and cooled to 0° C. The solutionwas stirred at 0° C. for seven hours and at room temperature for 40.5hours. The resultant solution was heated to 50° C. for 34.5 hours andleft at room temperature for two days. The mixture was evaporated andthe residue was chromatographed on silica gel (5 g) eluting with 5 to10% acetone in dichloromethane to afford p-nitrobenzyl4-[(2R,3S)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(124 mg).

IR (CH₂ Cl₂): 3390, 1765, 1745, 1715, 1605, 1525, 1345 cm⁻¹.

NMR (CDCl₃) δ: 1.46 (d, J=6.5 Hz, 3H), 3.00 (m, 2H), 3.10 (dd, J=2.5, 5Hz, 1H), 3.60 (s, 3H), 3.85 (m, 1H), 5.16 (m, 1H; d, J=5 Hz uponirradiation at 1.46 ppm), 5.27 (s, 4H), 6.47 (br s, 1H), 7.51 (d, J=9Hz, 2H), 7.53 (d, J=9 Hz, 2H), 8.18 (d, J=9 Hz, 4H).

[α]_(D) ²² +28.13° C. (c=0.736, CHCl₃).

EXAMPLE 66 ##STR87##

A stream of ozone was bubbled into a solution of methyl3-methyl-2-[(3S,4R)-4-{2-(p-nitrobenzyloxycarbonylmethyl)allyl}-3-}(1R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]but-2-enoate(233 mg) in ethyl acetate (10 ml) at -78° C. until blue color appeared.After three minutes, the excess of ozone was removed by a stream ofnitrogen. The solution was diluted with ethyl acetate (20 ml) and washedwith a chilled aqueous sodium bisulfite (1.2 g) and brine. The organiclayer was dried over magnesium sulfate and evaporated to leave anamorphous solid (240 mg). This residue was dissolved in dichloromethane(3 ml) containing dimethyl sulfide (0.9 ml) and cooled to 0° C. Methanol(9 ml) was added and the solution was stirred at 0° C. for five hours,and at room temperature for nine hours under a nitrogen atmosphere. Themixture was then heated to 55° C. for 31 hours. The resultant solutionwas evaporated, and the residue was chromatographed on silica gel (6 g)eluting with 5-14% acetone in dichloromethane to give p-nitrobenzyl4-[(2R,3S)-3-{(1S)-1-(p-nitrobenzyloxycarbonyloxy)-ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(145 mg).

IR (CH₂ Cl₂): 3370, 1760, 1745, 1710, 1605, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.42 (d, J=6.5 Hz, 3H), 2.8-3.1 (m, 3H), 3.60 (s, 2H),3.94 (ddd, J=2.5,5,8 Hz, 1H), 5.11 (quintet, J=7 Hz, 1H), 5.26 (s, 4H),6.52 (brs, 1H), 7.50 (d, J=9 Hz, 2H), 7.52 (d, J=9 Hz, 2H), 8.17 (d, J=9Hz, 2H).

[α]_(D) ²² +21.83° (c=0.907, CHCl₃).

EXAMPLE 67 ##STR88##

1.55M Butyl lithium-hexane solution (1.66 ml) was added to a solution ofN-isopropylcyclohexylamine (0.29 ml) in tetrahydrofuran (3 ml) at -70°C., and the mixture was stirred for 20 minutes at -70° C. and allowed towarm up to 0° C. This mixture was added to a solution of methyl3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg) intetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 1hour at -70° C. and allowed to warm up to -30° C. during 30 minutes. 1NHydrochloric acid (3.6 ml) was added to the reaction mixture at -70° C.,and the mixture was diluted with ethyl acetate (30 ml). The solution waswashed with water and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was chromatographed on silica geleluting with a mixture of hexane and ethyl acetate (5:1-2:1) to givemethyl3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20mg); IR (CH₂ Cl₂): 1740, 1715 cm⁻¹ ; NMR (CDCl₃) δ: 1.23 (d, 3H, J=8Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz), 3.36 (dq, 1H,J=6, 8 Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H),5.4-5.9 (m, 2H); and methyl3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (28mg); IR (CH₂ Cl₂): 1740 cm⁻¹. NMR (CDCl₃) δ: 1.27 and 1.29 (a pair of d,3H, J=8 Hz), 1.83 (broad s, 3H), 2.1-2.9 (m, 2H), 2.85 (dq, 1H, J=2, 8Hz), 3.2-3.4 (m, 1H), 3.74 and 3.76 (a pair of s, 3H), 4.8-5.2 (m, 5H),5.5-6.0 (m, 1H); and a mixture of methyl3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2 -enoateand methyl3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (36mg): IR (CH₂ Cl₂): 1740 cm⁻¹.

EXAMPLE 68 ##STR89##

1.55M Butyl lithium-hexane solution (2.97 ml) was added to a solution ofN-isopropylcyclohexylamine (0.76 ml) in tetrahydrofuran (6 ml) at -70°C. and the mixture was stirred for 20 minutes at -70° C. This mixturewas added to a solution of methyl3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (210 mg) intetrahydrofuran (6 ml) during 3 minutes at -70° C., and the mixture wasstirred for 1 hour at -70° C. and for 30 minutes at -30° C. Ethyl iodide(0.37 ml) was then added to the reaction mixture at -70° C. and themixture was stirred for 1 hour at the same temperature and for 30minutes at -30° C. 1N Hydrochloric acid (10 ml) was added to thereaction mixture at -70° C. and the mixture was diluted with ethylacetate (120 ml). The solution was washed with water, brine, aqueoussodium bicarbonate and brine, dried over magnesium sulfate andevaporated in vacuo. Triethylamine (0.16 ml) was added to a solution ofthe residue in dichloromethane (2 ml) at 0° C., and the mixture wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with ethyl acetate (20 ml) and the solution was washed with 0.1Nhydrochloric acid, brine, aqueous sodium bicarbonate and brine driedover magnesium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel (5 g) eluting with a mixture of hexane andethyl acetate (10:1-2:1) to give 169 mg of a 2.3:1 mixture of methyl3-methyl-2-[(3R,4R)-3-ethyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate[(3R,4R)-isomer] and its (3S,4R)-isomer: IR (CH₂ Cl₂): 1740, 1720 cm⁻¹.NMR (CDCl₃) δ: 1.04 and 1.12 (a pair of t, 3H, J=8 Hz), 1.6-2.0 (m, 2H),1.96 (s, 3H), 2.20 (s, 3H), 2.2-2.61 (m, 2H), 2.80 and 3.14 (a pair ofdq, 1H, J=2.5, 7 Hz and J=6, 7.5H (2.3:1), 3.70 and 4.04 (a pair of dt,1H, J=2.5, 7 Hz and J=6, 7 Hz), 3.76 (s, 3H), 4.9-5.3 (m, 2H), 5.5-6.0(m, 1H).

EXAMPLE 69 ##STR90##

Methyl3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate[(3R,4R)-isomer] and its (3S,4R)-isomer were prepared in a similarmanner to that of Example 68.

For the (3R,4R)-isomer: IR (CH₂ Cl₂): 1740, 1710 cm⁻¹. NMR (CDCl₃) δ:1.32 (d, 3H, J=7.5 Hz), 1.93 (s, 1H), 1.19 (s, 1H), 2.36 (q, 2H, J=8Hz), 2.84 (dq, 1H, J=2.5, 7.5 Hz), 3.56 (dt, 1H, J-2.5, 8 Hz), 3.72 (s,3H), 4.9-6.3 (m, 2H), 5.5-6.0 (m, 1H).

For the (3S,4R)-isomer: IR (CH₂ Cl₂): 1740, 1715 cm⁻¹. NMR (CDCl₃) δ:1.23 (d, 3H, J=8 Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz),3.36 (dq, 1H, J=6, 8 Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz),4.9-5.2 (m, 2H), 5.4-5.9 (m, 2H).

EXAMPLE 70 ##STR91##

1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution ofN-isopropylcyclohexylamine (0.72 ml) in tetrahydrofuran (6 ml) at -70°C., and the mixture was stirred for 20 minutes at -70° C. This mixturewas added to a solution of methyl3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) intetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hourat -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added tothe reaction mixture at -70° C., and the mixture was stirred for 1 hourat -70° C. and for 30 minutes at -30° C.-15° C. 3N Hydrochloric acid wasadded to the reaction mixture at -70° C. and the mixture was dilutedwith ethyl acetate (200 ml). The solution was washed with water, brine,aqueous sodium bicarbonate and brine, dried over magnesium sulfate, andevaporated in vacuo. Triethylamine (0.15 ml) was added to a solution ofthe residue in dichloromethane (3 ml) at 0° C. and the mixture wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with ethyl acetate (20 ml) and the solution was washed with 0.1Nhydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine,dried over magnesium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel (10 g) eluting with a mixture of benzeneand acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate(100 mg); IR (CH₂ Cl₂): 1740, 1715 cm⁻¹. NMR (CDCl₃) δ: 1.31 (s, 3H),1.38 (s, 3H), 1.96 (s, 3H), 2.18 (s, 3H), 2.2-2.5 (m, 3H), 2.90 (d, 1H,J=3 Hz), 3.76 (s, 3H), 3.81 (dt, 1H, J=3, 7 Hz), 4.9-5.2 (m, 2H),5.5-6.0 (m, 1H) and methyl3-methyl-2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate(50 mg).

NMR (CDCl₃) δ: 1.39 (s, 3H), 1.52 (s, 3H), 1.99 (s, 3H), 2.19 (s, 3H),2.21 (broad s, 1H), 2.74 (t, 2H, J=7 Hz), 3.30 (d, 1H, J=6 Hz), 3.74 (s,3H), 4.12 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.5-5.9 (m, 1H).

EXAMPLE 71 ##STR92##

Methyl3-methyl-2-[(3S,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate[(3S,4R)-isomer] and methyl3-methyl-2-[(3R,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate[(3R,4R)-isomer] were prepared in a similar manner to that of Example70.

For the (3S,4R)-isomer: IR (CH₂ Cl₂): 1740, 1720 cm⁻¹. NMR (CDCl₃) δ:1.32 (d, 3H, J=7 Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.3-2.5 (m, 2H), 2.6(broad s, 1H), 2.90 (dd, 1H, J=7, 2.5 Hz), 3.76 (s, 3H), 3.82 (dt, 1H,J=2.5, 6 Hz), 4.0-4.3 (m, 1H), 5.0-5.2 (m, 2H), 5.5-6.0 (m, 1H).

For the (3R,4R)-isomer: IR (CH₂ Cl₂): 1740, 1720 cm⁻¹. NMR (CDCl₃) δ:1.22 (d, 3H, J=5.5 Hz), 2.00 (s, 3H), 2.20 (s, 3H), 2.2-2.8 (m, 3H),3.24 (dq, 1H, J=4.5, 5.5 Hz), 3.75 (s, 3H), 3.9-4.3 (m, 2H), 4.9-5.2 (m,2H), 5.5-6.0 (m, 1H).

EXAMPLE 72 ##STR93## and its other isomers

1.55M Butyl lithium-hexane solution (5.63 ml) was added to a solution ofN-isopropylcyclohexylamine (1.44 ml) in tetrahydrofuran (10 ml) at -70°C. The solution was stirred for 20 minutes at -70° C. and allowed towarm up to -20° C. during 5 minutes. This mixture was added to asolution of methyl3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (650 mg) intetrahydrofuran (10 ml) during 15 minutes at -70° C., and the mixturewas stirred for 1 hour at -70° C. and for 30 minutes at -30° C. Asolution of acetaldehyde (187 mg) in tetrahydrofuran (4.4 ml) was addedto the reaction mixture at -70° C. The mixture was stirred for 1 hour at-70° C. and for 30 minutes at -30° C. 1N Hydrochloric acid (20 ml) wasadded to the reaction mixture at -70° C. and the mixture was dilutedwith ethyl acetate (250 ml). The solution was washed with brine, aqueoussodium bicarbonate and brine, dried over magnesium sulfate andevaporated in vacuo.

The residue was chromatographed on silica gel (20 g) eluting with amixture of benzene and acetone (10:1-3:1) to give methyl3-methyl-2-{(3S,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl}but-2-enoate(278 mg) [(3S,4R)-isomer] and its other isomers (257 mg).

For the (3S,4R)-isomer: IR (CH₂ Cl₂): 1740, 1720 cm⁻¹. NMR (CDCl₃) δ:1.32 (d, 3H, J=7 Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.3-2.5 (m, 2H), 2.6(broad s, 1H), 2.90 (dd, 1H, J=7, 2.5 Hz), 3.76 (s, 3H), 3.82 (dt, 1H,J=2.5, 6 Hz), 4.0-4.3 (m, 1H), 5.0-5.2 (m, 2H), 5.5-6.0 (m, 1H).

EXAMPLE 73 ##STR94##

4-Dimethylaminopyridine (79 mg) and 4-nitrobenzyl chloroformate (90 mg)were added to a solution of a 1:3 mixture of methyl3-methyl-2-[(3S,4R)-3-(1RS)-1-hydroxyethyl)-2-oxo-allylazetidin-1-yl]but-2-enoate(86 mg) in dichloromethane (4 ml) at 0° C. and the mixture was stirredfor three hours at 0° C. The reaction mixture was diluted with ethylacetate (50 ml), and washed in turn with 0.1N hydrochloric acid (20 ml),brine, aqueous sodium bicarbonate and brine. The organic layer was driedover magnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (2 g) eluting with hexane and ethylacetate (5:1-2:1) to give a 1:3 mixture of methyl3-methyl-2-{(3S,4R)-3-[(1Rs)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl}but-2-enoate(122 mg) as an oil.

IR (CH₂ Cl₂): 1745, 1715, 1520 cm⁻¹. NMR (CDCl₃) δ: 1.48 (d, 3H, J=7Hz), 1.96 (s, 3H), 1.20 (s, 3H), 2.2-2.6 (m, 2H), 3.03 and 3.18 (dd,J=7.5, 2.5 Hz and dd, J=5, 2.5 Hz, 1H (1:3)), 3.75 (s, 3H), 3.8-4.0 (m,1H), 5.0-5.3 (m, 2H), 5.27 (s, 2H), 5.5-5.9 (m, 1H), 7.89 (A₂ B₂, 4H,J=8.5 Hz).

EXAMPLE 74 ##STR95##

A 1:3 mixture of methyl3-methyl-2-[(3S,4R)-3-[(1RS)-1-hydroxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(55 mg) was dissolved in tetrahydrofuran (2 ml) and triphenylphosphine(135 mg) and formic acid (19.4 μl) were added to the mixture. Thismixture was cooled to 0° C. and a solution of diethyl azodicarboxylate(81 μl) in tetrahydrofuran (1 ml) was added. After stirring at the sametemperature overnight, the mixture was diluted with ethyl acetate (30ml), washed with aqueous sodium bicarbonate and brine, dried overmagnesium sulfate and evaporated. The residue was chromatographed onsilica gel (5 g) eluting with hexane and ethyl acetate (10:1-2:1) togive 25 mg of methyl3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]-but-2-enoate.

IR (CH₂ Cl₂): 1745, 1720 cm⁻¹. NMR (CDCl₃) δ: 1.42 (d, 3H, J=6 Hz), 1.96(s, 3H), 2.20 (s, 3H), 2.38 (q, 2H, J=6 Hz), 3.00 (dd, 1H, J=7.5, 2.5Hz), 3.76 (s, 3H), 3.7-4.0 (m, 1H), 4.9-5.2 (m, 2H), 5.3-5.9 (m, 2H),8.00 (s, 1H).

EXAMPLE 75 ##STR96##

Methyl3-methyl-2-[(3S,4R)-3-[(1R)-1-formyloxyethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(23 mg) was dissolved in methanol (1 ml) and cooled to 0° C. To thissolution was added a solution of sodium methoxide in methanol (0.49M,0.16 ml) and the mixture was stirred for 1 hour at the same temperature.An additional 0.08 ml of the sodium methoxide solution was added and themixture was stirred for 30 minutes at the same temperature. Acetic acid(2 drops) was then added and the mixture was evaporated. The residue wasdissolved in ethyl acetate, washed with aqueous sodium bicarbonate andbrine, dried over magnesium sulfate and evaporated. The residue waspurified by preparative thin layer chromatography (silica gel)developing with methylene chloride and ethyl acetate (2:1) to givemethyl3-methyl-2-[(3S,4R)-3-(1R)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate(20 mg),

IR (CH₂ Cl₂): 3550, 1740, 1710 cm⁻¹. NMR (CDCl₃) δ: 1.32 (d, 3H, J=7Hz), 1.96 (s, 3H), 2.20 (s, 3H), 2.3-2.6 (m, 2H), 2.90 (dd, 1H, J=7, 2.5Hz), 3.76 (s, 3H), 4.00 (dt, 1H, J=2.5, 6.5 Hz), 4.1-4.4 (m, 1H),5.0-5.3 (m, 2H), 5.5-6.0 (m, 1H).

EXAMPLE 76 ##STR97##

Methyl3-methyl-2-[(3S,4R)-3-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoatewas prepared in a similar manner to that of Example 73.

IR (CH₂ Cl₂) δ: 1745, 1715, 1520 cm⁻¹. NMR (CDCl₃) δ: 1.45 (d, 3H, J=6Hz), 1.94 (s, 3H), 2.19 (s, 3H), 2.37 (q, 2H, J=6 Hz), 3.01 (dd, 1H,J=7.5, 2.5 Hz), 3.76 (s, 3H), 3.92 (dt, 1H, J=2.5 6 Hz), 4.9-5.3 (m,3H), 5.4-5.8 (m, 1H), 7.83 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 77 ##STR98##

Silver tetrafluoroborate (205 mg) was added to a stirred solution of4-nitrobenzyl 3-(trimethylsilylmethyl)but-3-enoate (422 mg) and a 4:1mixture of methyl2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoateand its (3S,4S)-isomer (305 mg) in dichloromethane (3 ml) at -78° C.under a nitrogen atmosphere. The mixture was gradually allowed to warmto 0° C. during 40 minutes and kept at the same temperature for onehour. The resulting mixture was diluted with dichloromethane (1 ml) andstirred at 0° C. for 30 minutes and at room temperature for 30 minutes.The mixture was diluted with ethyl acetate (10 ml) and a saturatedaqueous solution of sodium chloride (4 ml) was added. The mixture wasbrought to pH 7 with a saturated aqueous solution of sodium bicarbonateand filtered through diatomaceous earth. The filtrate was diluted withethyl acetate (30 ml). The organic layer was separated, washed withbrine, dried over magnesium sulfate, and evaporated. The residue waschromatographed on silica gel (12 g, eluting with 1 to 5% acetone indichloromethane) to give 120 mg of the desired product contaminated withsome impurities. Further purification on a TLC plate (20 cm×20 cm×2 mm,1:1 hexane-ethyl acetate) afforded 100 mg (22.8%) of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4-nitrobenzyloxycarbonyl-methyl)allyl]-2-oxoazetidin-1-yl]but-2-enoate:IR (CH₂ Cl₂): 1740, 1720(sh), 1520, and 1350 cm⁻¹ ; NMR (CDCl₃), δ: 1.65(s, 3H), 1.69 (s, 3H), 1.98 (s, 3H), 2.19 (s, 3H), 2.48 (brd, J=7 Hz,2H), 3.13 (s, 2H), 3.44 (d, J=2.5 Hz, 1H), 3.76 (s, 3H), 4.24 (dt, J=2.5and 7 Hz, 1H), 5.01 (m, 2H), 5.19 (s, 2H), 5.22 (s, 2H), 7.52 (d, J=9Hz, 2H), 7.56 (d, J= 9 Hz, 2H), and 8.22 (d, J=9 Hz, 4H).

EXAMPLE 78 ##STR99##

In a manner similar to that of Example 77, 258 mg of methyl2-[(3S,4R)-4-chloro-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxoazetidin-1-yl]-3-methylbut-2-enoateafforded 70.0 mg (18.9%) of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4-nitrobenzyloxycarbonylmethyl)allyl]-2-oxoazetidine-1-yl]but-2-enoate.

EXAMPLE 79 ##STR100##

A stream of ozone was bubbled into a solution of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-[2-(4-nitrobenzyloxycarbonylmethyl)allyl]-2-oxoazetidin-1-yl]but-2-enoate(163 mg) in ethyl acetate (10 ml) at -78° C. until a permanent bluecolor developed. After three minutes the excess ozone was removed bybubbling nitrogen. The solution was warmed and poured into a mixture ofethyl acetate (10 ml) and a dilute aqueous solution of sodium bisulfite(900 mg). The mixture was shaken and the organic layer was separated.The solution was washed with brine, dried over magnesium sulfate andevaporated to leave 158 mg of an amorphous solid. This residue wasdissolved in dichloromethane (2.5 ml) and cooled to 0° C. Dimethylsulfide (0.7 ml) and methanol (7.5 ml) were added. The solution wasstirred at 0° C. for 8 hours and left at ambient temperature for 15hours under a nitrogen atmosphere. The mixture was then heated to 55° C.for 26 hours and evaporated. The residue was chromatographed on a TLCplate (20 cm×20 cm×2 mm, 10% acetone in dichloromethane) to give 79 mg(58.3%) of 4-nitrobenzyl4-[(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]-3-oxobutanoate:IR (CH₂ Cl₂): 3370, 1760, 1740, 1710, 1520, and 1345 cm⁻¹ ; NMR (CDCl₃)δ: 1.57 (s, 3H), 1.62 (s, 3H), 2.4-3.2 (m, small signals), 2.9 (m,1.5H), 3.34 (d, J=3 Hz, 1H), 3.56 (s, 2H), 3.96 (m, 1H), 5.15 (s, 2H),5.24 (s, 2H), 6.42 (brs, 1H), 7.50 (d, J=9 Hz, 4H), and 8.16 (d, J=9 Hz,4H).

(The product may exist as a equilibrium mixture of the keto- andenol-form.)

EXAMPLE 80 ##STR101##

To a solution of (3R,4R)-4-(2-oxoethyl)-3-phthalimidoazetidin-2-one (52mg) in a mixture of methanol (3ml) and dichloromethane (1 ml) was addeda solution of sodium borohydride (8 mg) in methanol (2 ml) at 0° C.during one hour. The reaction was quenched by addition of acetic acid(two drops). After evaporation in vacuo, the residue was chromatographedon silica gel (1.6 g; eluting with 3 to 5% methanol in dichloromethane)to give 32 mg of crude crystals. Crystallization from a mixture ofmethanol and ether afforded 27 mg(51.5%) of(3R,4R)-4-(2-hydroxyethyl)-3-phthalimidoazetidin-2-one. IR (Nujol):3350(br), 3250, 1750, and 1705 cm⁻¹ ; NMR (DMSO-d₆) δ: 1.79 (q, J=6 Hz,2H), 3.46 (m, 2H), 3.97 (dt, J=2.5 and 6 Hz, 1H), 4.47 (brs, 1H), 4.89(d, J=2.5 Hz, 1H), 7.86 (s, 4H), and 8.42 (brs, 1H).

EXAMPLE 81 ##STR102##

Boron trifluoride etherate (5 μl) was added to a suspension of(3R,4R)-4-(2-hydroxyethyl)-3-phthalimidoazetidin-2-one (126 mg) and2,2-dimethoxypropane (74 μl) in dichloromethane (3 ml) at ambienttemperature. The mixture was stirred for two hours. Additionaldimethoxypropane (50 μl) was added and the mixture was stirred for anadditional 1.5 hours. The resulting solution was poured into a saturatedaqueous solution of sodium chloride and sodium bicarbonate and extractedtwice with dichloromethane. The combined extracts were dried overmagnesium sulfate and evaporated to give a crystalline solid.Chromatography on silica gel (4 g; eluting with 3% acetone indichloromethane) and washing the crystals with ether afforded 100 mg of(6R,7R)-2,2-dimethyl-7-phthalimido-1-aza-3-oxabicyclo[4.2.0]-octan-8-one:IR (CH₂ Cl₂): 1770 and 1720 cm⁻¹ ; NMR (CDCl₃) δ: 1.56 (s, 3H), 1.81 (s,3H), 1.7-2.0 (m, 2H), 3.7-4.1 (m, 3H), 5.01 (d, J=2 Hz, 1H), and 7.5-7.9(m, 4H).

EXAMPLE 82 ##STR103##

N,N-Dimethylaminopropylamine (91 μl) was added to a solution of(6R,7R)-2,2-dimethyl-7-phthalimido-1-aza-3-oxabicyclo[4.2.0]octan-8-one(80 mg) in a mixture of methanol (1.4 ml) and dichloromethane (0.7 ml)at 0° C. under a nitrogen atmosphere. The solution was stirred at thesame temperature for two hours and left at ambient temperature for 24hours. The mixture was evaporated and the residue was chromatographed onsilica gel (1.5 g; eluting with 3 to 5% methanol in dichloromethane) togive 27 mg (59.5%) of(6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one: IR(CH₂ Cl₂): 3100-3600 (broad) and 1735 cm⁻¹ ; NMR (CDCl₃) δ: 1.41 (s,3H), 1.72 (s, 3H), 1.5-2.1 (m, 4H), 3.34 (ddd, J=2, 5 and 10 Hz, 1H),and 3.7-3.9 (m, 3H).

EXAMPLE 83 ##STR104##

To a solution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(106.9 mg) in tetrahydrofuran (2.1 ml) was added dropwise a solution ofn-butyl lithium (0.375 ml of 1.38M solution in hexane) at -78° C. Afterstirring for 15 minutes at -78° C., the reaction mixture was added witha solution of acetone (0.0385 ml) in tetrahydrofuran (0.3465 ml) at -78°C. After stirring for 25 minutes at -78° C., the reaction mixture wasadded with acetic acid (0.0493 ml) at -78° C., diluted with ethylacetate (30 ml), and washed with chilled brine (10 ml), aqueous sodiumbicarbonate (10 ml), brine (10 ml), and saturated aqueous sodiumchloride (10 ml). After drying over magnesium sulfate, the ethyl acetateextract was filtered and evaporated in vacuo. The residual oil waschromatographed on silica gel (1.2 g) eluting with a mixture of ethylacetate and hexane (1:5-1:3) to give methyl2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(96.5 mg) as an oil.

IR (CH₂ Cl₂): 2115, 1770, 1720 cm⁻¹. NMR (CDCl₃) δ: 1.40 (s, 3H), 1.53(s, 3H), 1.97 (s, 3H), 2.23 (s, 3H), 2.39 (s, 1H), 2.53 (t, 2H, J=7 Hz),3.76 (s, 3H), 4.24 (t, 1H), J=7 Hz), 5.0-5.3 (m, 2H), 5.5-5.9 (m, 1H).

EXAMPLE 84 ##STR105##

Tributyltin hydride (0.707 ml) was added to a mixture of methyl2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(630 mg) and azobisisobutyronitrile (34 mg) in benzene (6 ml) at roomtemperature, and the mixture was refluxed for 15 minutes. The reactionmixture was cooled and chromatographed on silica gel (20 g) eluting witha mixture of hexane and ethyl acetate (3:1-1:1) to give a 3:1 mixture(559 mg) of methyl2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoateand its (3R,4R)-isomer.

IR (CH₂ Cl_(z)): 1740, 1715 cm⁻¹. NMR (CDCl₃) δ: 1.31 (s, 3H×3/4), 1.38(s, 3H), 1.52 (s, 3H×1/4), 1.96 (s, 3H×3/4), 1.99 (s, 3H×1/4), 2.18 (s,3H), 2.1-2.8 (m, 2H), 2.90 (d, 1H×3/4, J=3 Hz), 3.30 (d, 1H×1/4, J=6Hz), 3.74 (s, 3H×1/4), 3.76 (s, 3H×3/4), 3.8-4.2 (m, 1H), 4.9-5.2 (m,2H), 5.5-5.9 (m, 1H).

EXAMPLE 85 ##STR106##

Potassium carbonate (113 mg) was added to a solution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(203 mg) in acetone (2 ml) at 0° C., and the mixture was stirred for 20hours at ambient temperature.

Potassium carbonate (210 mg) and acetone (1.5 ml) were added to thereaction mixture at ambient temperature, and the mixture was stirred for18 hours at ambient temperature. The reaction mixture was diluted withdichloromethane (3 ml) and filtered. The filtrate was evaporated invacuo, and the residue was chromatographed on silica gel (2 g) elutingwith a mixture of hexane and ethyl acetate (3:1) to give methyl2-[(3R,4R)-3-allyl-5,5-dimethyl-1-oxo-2,8-diaza-6-oxaspiro[3,4]oct-5-en-2-yl]-3-methylbut-2-enoate(120 mg).

IR (CH₂ Cl₂): 1755, 1715, 1610 cm⁻¹.

NMR (CDCl₃) δ: 1.40 (s, 3H), 1.64 (s, 3H), 2.01 (s, 3H), 2.23 (s, 3H),2.3-2.6 (m, 2H), 3.77 (s, 3H), 4.11 (t, 1H, J=7 Hz), 4.9-5.2 (m, 2H),5.4-5.8 (m, 1H), 6.94 (s, 1H).

EXAMPLE 86 ##STR107##

A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (17 μl) in methylenechloride (0.1 ml) was added to a solution of methyl2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(17 mg) in methylene chloride (1 ml) and acetone (1 ml) at 0° C., andthe mixture was stirred for 20 hours at ambient temperature. Acetic acid(2 drops) was added to the reaction mixture at 0° C., and the mixturewas evaporated in vacuo. The residue was dissolved in ethyl acetate (20ml), and the solution was washed with 10% aqueous phosphoric acid,brine, phosphate buffer (pH 6.9), aqueous sodium bicarbonate and brine,dried over magnesium sulfate and evaporated in vacuo to give methyl2-[(3R,4R)-3-allyl-5,5-dimethyl-1-oxo-2,8-diaza-6-oxaspiro[3,4]oct-7-en-2-yl]-3-methylbut-2-enoate(19 mg) as crude crystals.

EXAMPLE 87 ##STR108##

A solution of n-butyl lithium (0.42 ml of 1.55M solution in hexane) wasadded to a solution of methyl2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(150 mg) in tetrahydrofuran (3 ml) during 3 minutes at -70° C. and themixture was stirred for 5 minutes at -70° C. A solution of p-nitrobenzylchloroformate (161 mg) in tetrahydrofuran (1.6 ml) was added to themixture during 5 minutes at -70° C. and the mixture was stirred for 15minutes at -70° C. The mixture was allowed to warm to 0° C. during 30minutes and stirred for 2 hours at 0° C. Acetic acid (0.037 ml) wasadded to the mixture at 0° C. and the mixture was evaporated in vacuo.The residue was dissolved in ethyl acetate (50 ml), and was washed withwater (10 ml), 10% phosphoric acid (10 ml), phosphate buffer (pH 7.0)(10 ml×2), aqueous sodium bicarbonate and brine. The organic layer wasdried over magnesium sulfate and evaporated in vacuo. The residue waschromatographed on silica gel (10 g) eluting with a mixture of hexaneand ethyl acetate (5:1-1:1) to give methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(135 mg) as an oil.

IR (CH₂ Cl₂): 1740, 1710, 1520, 1345 cm⁻¹.

NMR (CDCl₃) δ: 1.66 (s, 3H), 1.69 (s, 3H), 1.97 (s, 3H), 2.19 (s, 3H),2.2-2.5 (m, 2H), 3.40 (d, 1H), J=2.5 Hz), 3.71 (s, 3H), 4.03 (dt, 1H,J=2.5, 6.5 Hz), 4.9-5.2 (m, 2H), 5.19 (s, 2H), 5.5-5.9 (m, 1H), 7.90 (A₂B₂, 4H, J=9 Hz)

EXAMPLE 88 ##STR109##

A solution of n-butyl lithium (0.46 ml) of 1.38M solution in hexane) wasadded to a solution of methyl2-[3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(150 mg) in tetrahydrofuran (3 ml) at -70° C. and the mixture wasstirred for 15 minutes at -70° C. A solution of p-nitrobenzylchloroformate (161 mg) in tetrahydrofuran (3.2 ml) was added to thereaction mixture at -70° C. and the mixture was stirred for 10 minutesat -70° C. The mixture was allowed to warm to 0° C. during 30 minutesand stirred at 0° C. for 1.5 hours. Acetic acid (0.043 ml) was added tothe mixture at 0° C. and the mixture was evaporated in vacuo. Theresidue was dissolved in ethyl acetate (30 ml) and the solution waswashed with brine, aqueous sodium bicarbonate, and brine. The organiclayer was dried over magnesium sulfate and evaporated in vacuo. Theresidue was chromatographed on silica gel (10 g) eluting with a mixtureof hexane and ethyl acetate (10:1-3:1) to give methyl3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(123 mg) as an oil.

IR (CH₂ Cl₂): 1745, 1720, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.70 (s, 3H), 1.81 (s, 3H), 2.01 (s, 3H), 2.10 (s, 3H),2.64 (t, 2H), J=7 Hz), 3.59 (d, 1H, J=5 Hz), 3.74 (s, 3H), 4.17 (dt, 1H,J=5,7 Hz), 4.9-5.3 (m, 2H), 5.21 (s, 2H), 5.5-5.9 (m, 1H), 7.87 (A₂ B₂,4H, J=9 Hz).

EXAMPLE 89 ##STR110##

Ozone was bubbled into a solution of methyl3-methyl-2-[(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(50 mg) in ethyl acetate (3 ml) at -70° C. until a blue color appeared.After stirring for 15 minutes at the same temperature, the mixture waspurged with nitrogen. The reaction mixture was diluted with ethylacetate (20 ml) and the solution was washed with an aqueous solution ofsodium bisulfite and sodium sulfite (2:1), and brine. The organic layerwas dried over magnesium sulfate and evaporated in vacuo.

The residue was dissolved in methylene chloride (3 ml) andm-chloroperbenzoic acid (48 mg) was added to the solution at 0° C. Themixture was stirred for 24 hours at ambient temperature. Additionalm-chloroperbenzoic acid (48 mg) was added, and the mixture was stirredfor 24 hours at ambient temperature. The mixture was evaporated invacuo. The residue was dissolved in methanol (3 ml) and the mixture washeated for 24 hours at 50° C. The mixture was evaporated in vacuo andthe residue was chromatographed on silica gel (4 g) eluting with amixture of methylene chloride and methanol (20:1-5:1) to give{(2R,3S)-3-[1-methyl-1-(4-nitrobenzoyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}aceticacid (43 mg) as an oil.

IR (CH₂ Cl₂): 1740, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.60 (broad s, 6H), 2.3-2.8 (m, 2H), 3.36 (broad s, 1H),3.7-4.0 (m, 1H), 5.16 (s, 2H), 7.1-7.3 (broad, 1H), 7.84 (A₂ B₂, 4H, J=8Hz), 9.1-9.6 (broad, 1H).

EXAMPLE 90 ##STR111##

A solution of diazomethane in ether (1 ml) was added to a solution of[(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]-aceticacid (29 mg) in a mixture of methylene chloride (1 ml) and methanol (1ml) at 0° C. and the mixture was stirred for 15 minutes at 0° C. Aceticacid (1 drop) was added to the mixture at 0° C. and the mixture wasevaporated in vacuo. The residue was chromatographed on silica gel (1 g)eluting with a mixture of methylene chloride and ethyl acetate (10:1) togive methyl[(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]acetate(31 mg).

IR (CH₂ Cl₂): 1760, 1740, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.61(s, 3H), 1.65 (s, 3H), 2.4-2.6 (m, 2H), 3.36 (d, 1H,J=3 Hz), 3.69 (s, 3H), 3.8-4.0 (m, 1H), 5.17 (s, 2H), 6.40 (s, 1H), 7.87(A₂ B₂, 4H, J=9 Hz).

EXAMPLE 91 ##STR112##

Ozone was bubbled into a solution of methyl2-[(3S,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(159 mg) in ethyl acetate (5 ml) at -70° C. until a blue color appeared.After stirring for 15 minutes at same temperature, the mixture waspurged with nitrogen. The mixture was diluted with ethyl acetate (30 ml)and the solution was washed with an aqueous solution of sodium bisulfiteand sodium sulfite (2:1). The aqueous layer was extracted with ethylacetate (10 ml). The combined organic layers were washed with brine,dried over magnesium sulfate, and evaporated in vacuo.

The residue was dissolved in methylene chloride (3 ml) andm-chloroperbenzoic acid (244 mg) was added at ambient temperature. Themixture was refluxed for 24 hours and evaporated in vacuo. The residuewas dissolved in methanol (3 ml) and m-chloroperbenzoic acid (244 mg)was added. The mixture was heated at 50° C. for 20 hours and evaporatedin vacuo. The residue was chromatographed on silica gel (3 g) elutingwith a mixture of methylene chloride and methanol (9:1-2:1) to give[(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (25mg).

IR (CH₂ Cl₂): 1750, 1730, 1710 cm⁻¹.

NMR (CD₃ OD) δ: 1.28 (s, 3H), 1.32 (s, 3H), 2.5-2.7 (m, 2H), 2.90 (d,1H, J=2.5 Hz), 3.8-4.0 (m, 1H).

EXAMPLE 92 ##STR113##

A solution of diazomethane in ether (2 ml) was added to a solution of[(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetic acid (23mg) in methanol (3 ml) at 0° C. and the mixture was stirred for an hourat 0° C. Acetic acid (2 drops) was added to the mixture at 0° C. and themixture was evaporated in vacuo to give methyl[(2R,3S)-3-(1-hydroxy-1-methylethyl)-4-oxoazetidin-2-yl]acetate (25 mg).

IR (CH₂ Cl₂): 1760, 1735 cm⁻¹.

NMR (CD₃ OD) δ: 1.28 (s, 3H), 1.34 (s, 3H), 2.6-2.8 (m, 2H), 2.89 (d,1H, J=2.5 Hz), 3.70 (s, 3H), 3.8-4.0 (m, 1H).

EXAMPLE 93 ##STR114##

Ozone was bubbled into a solution of methyl3-methyl-2-[(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]but-2-enoate(120 mg) in ethyl acetate (5 ml) at -70° C. until a blue color appeared.After stirring for 15 minutes at the same temperature, the mixture waspurged with nitrogen. The reaction mixture was diluted with ethylacetate (30 ml) and the solution was washed with an aqueous solution ofsodium bisulfite and sodium sulfite (2:1), and brine. The organic layerwas dried over magnesium sulfate and evaporated in vacuo. The residuewas dissolved in methylene chloride (3 ml) and m-chloroperbenzoic acid(112 mg) was added at 0° C. The mixture was stirred for 24 hours atambient temperature, and evaporated in vacuo. The residue was dissolvedin methanol (5 ml) and m-chloroperbenzoic acid (112 mg) was added. Themixture was heated at 50° C. for 2 days and evaporated in vacuo. Theresidue was chromatographed on silica gel (6 g) eluting with a mixtureof methylene chloride and methanol (20:1-5:1) to give[(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl]aceticacid (43 mg) as an oil.

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.60 (s, 3H), 1.72 (s, 3H), 2.5-3.2 (m, 2H), 3.4-3.7 (m,1H), 3.9-4.2 (m, 1H), 5.18 (s, 2H), 7.82 (A₂ B₂, 4H, J=9 Hz), 8.4-9.1(broad, 1H).

EXAMPLE 94 ##STR115##

Ozone was bubbled into a solution of methyl2-[(3R,4R)-3-(1-hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(240 mg) in ethyl acetate (5 ml) at -70° C. until a blue color appeared.After stirring for 15 minutes at -70° C. The mixture was purged withnitrogen. The mixture was diluted with ethyl acetate (30 ml) and thesolution was washed with aqueous saturated sodium bisulfite. The aqueouslayer was extracted with chloroform (10 ml). The combined organic layerwas dried over magnesium sulfate and evaporated in vacuo. The residuewas dissolved in methylene chloride (3 ml) and m-chloroperbenzoic acid(368 mg) was added at ambient temperature. After stirring for 20 hoursat ambient temperature, the mixture was evaporated in vacuo. The residuewas dissolved in methanol (5 ml) and m-chloroperbenzoic acid (368 mg)was added. The mixture was heated at 50° C. for 2 days, left for a dayat room temperature, and evaporated in vacuo. The residue waschromatographed on silica gel (3 g) eluting with a mixture of methylenechloride and methanol (10:1-2:1) to give(1R,6R)-2,2-dimethyl-4,8-dioxo-7-aza-3-oxabicyclo-[4.2.0]octane (48 mg).

m.p. 180°-182° C.

IR (CH₂ Cl₂): 1775, 1740 cm⁻¹.

NMR (CD₃ OD) δ: 1.46 (s, 3H), 1.60 (s, 3H), 2.82 (dd, 1H, J=17 Hz, 2Hz), 2.96 (dd, 1H, J=17 Hz, 4 Hz), 3.50 (d, 1H, J=5 Hz), 4.18 (ddd, 1H,J=5 Hz, 4 Hz, 2 Hz), 4.62 (s, 3H).

Elemental Analysis: C 56.42%, H 6.26%, N 8.24%. Calcd for C₈ H₁₁ NO₃ : C56.80%, H 6.55%, N 8.28%.

EXAMPLE 95 ##STR116##

To a solution of methyl[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (7.0g) in methylene chloride (110 ml) were added 2,6-lutidine (4.11 ml) andbenzyl chloroformate (5.03 ml) at 0° C. and the mixture was stirred for30 minutes at 0° C. The reaction mixture was diluted with ethyl acetate(800 ml) and the solution was washed with diluted hydrochloric acid,brine, aqueous saturated sodium bicarbonate, and brine. The organiclayer was dried over magnesium sulfate and evaporated in vacuo. Theresidue was chromatographed on silica gel (200 g) eluting with a mixtureof methylene chloride and ethyl acetate (20:1-4:1) to give methyl[(3R,4R)-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(10.7 g) as an oil.

IR (CH₂ Cl₂): 3380, 1750, 1720 cm⁻¹.

NMR (CD₃ OD) δ: 1.95 (s, 3H), 2.17 (s, 3H), 2.44 (t, 2H, J=7 Hz), 3.73(s, 3H), 4.06 (dt, 1H, J=2.5, 7 Hz), 4.44 (d, 1H, J=2.5 Hz), 4.9-5.2 (m,2H), 5.10 (s, 2H), 5.5-6.0 (m, 1H), 7.34 (s, 5H).

EXAMPLE 96 ##STR117##

Ozone was bubbled into a solution of methyl[(3R,4R)-3-benzyloxycarbonylamino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(5 g) in methanol (100 ml) at -60° C. until a blue color was appeared.After stirring for 10 minutes at -60° C., the mixture was purged withnitrogen. Dimethyl sulfide (5 ml) was added to the mixture at -60° C.and the mixture was allowed to warm to 0° C. during 15 minutes. Afterstirring for an hour at 0° C., the mixture was left for 20 hours atambient temperature. Dimethyl sulfide (2 ml), trimethyl orthoformate (5ml), and p-toluenesulfonic acid monohydrate (150 mg) were added to themixture and the mixture was heated at 50° C. for 6 hours. Pyridine(0.076 ml) was added to the reaction mixture at ambient temperature andthe mixture was evaporated in vacuo. The residue was dissolved in ethylacetate and the solution was washed with water, dilute hydrochloricacid, brine, aqueous sodium bicarbonate, and brine.

The organic layer was dried over magnesium sulfate, and evaporated invacuo. The residue was dissolved in methanol (100 ml), and the solutionwas heated at 50° C. for 3 hours and left at ambient temperature for 2days. The mixture was evaporated in vacuo and the residue waschromatographed on silica gel (100 g) eluting with a mixture ofmethylene chloride and acetone (10:1-2:1) to give(3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one(2.83 g) as an oil.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

NMR (acetone-d₆) δ: 1.8-2.2 (m, 2H), 3.30 (s, 6H), 3.66 (dt, 1H, J=3, 7Hz), 4.42 (dd, 1H, J=3, 9 Hz), 4.51 (t, 1H, J=5.5 Hz), 5.12 (s, 2H), 7.0(brs, 1H), 7.2 (m, 1H), 7.40 (s, 5H).

EXAMPLE 97 ##STR118##

To a solution of(3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one(2.15 g) in acetic acid (35.2 ml) were added dimethylsulfide (2 ml) andwater (8.8 ml) at ambient temperature and the mixture was heated at 50°C. for 4.5 hours. The reaction mixture was evaporated in vacuo and theresidue was dissolved in xylene (40 ml). The mixture was evaporated invacuo and the residue was chromatographed on silica gel (10 g) elutingwith a mixture of methylene chloride and acetone (5:1-2:1) to give acrystalline solid. This crude crystals were washed with ether and driedover phosphorous pentoxide to give(3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (863 mg).

IR (CH₂ Cl₂): 1780, 1720 cm⁻¹.

NMR (acetone-d₆) δ: 2.7-3.1 (m, 2H), 3.8-4.0 (m, 1H), 4.43 (dd, 1H, J=2,8 Hz), 5.07 (s, 2H), 6.9-7.2 (broad, 1H), 7.30 (s, 5H), 9.69 (s, 1H).

EXAMPLE 98 ##STR119##

To a solution of(3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (850 mg)in methanol (17 ml) was added sodium borohydride (123 mg) at 0° C. andthe mixture was stirred for 15 minutes at 0° C. Acetic acid (0.37 ml)was added to the mixture at 0° C. After stirring for 15 minutes at 0°C., the mixture was evaporated in vacuo. The residue was chromatographedon silica gel (17 g) eluting with a mixture of methylene chloride andmethanol (20:1-10:1) to give a crystalline solid. This crude crystalswere washed with ether and dried over phosphorous pentoxide to give(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (748mg).

mp. 120°-121° C.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

NMR (acetone-d₆) δ: 1.7-2.11 (m, 2H), 2.82 (s, 1H), 3.5-3.8 (m, 3H),4.39 (dd, 1H, J=3, 8 Hz), 5.05 (s, 2H), 6.9-7.3 (broad, 2H), 7.30 (s,5H).

EXAMPLE 99 ##STR120##

A solution of(3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one(0.60 g) in a mixture of tetrahydrofuran (10 ml) and 0.5N hydrochloricacid (2 ml) was heated at 50° C. for 1 hour. The mixture was cooled to0° C. and 1N aqueous sodium bicarbonate (1.2 ml) was added to themixture at 0° C. After stirring for 5 minutes at 0° C., sodiumborohydride (0.10 g) was added to the mixture at 0° C. After stirringfor 15 minutes at 0° C., acetone (0.77 ml) and acetic acid (0.30 ml)were added to the mixture at 0° C. The mixture was evaporated in vacuoand the residue was dissolved in methylene chloride (60 ml). Thesolution was dried over magnesium sulfate and evaporated in vacuo. Theresidue was dissolved in xylene (20 ml) and the solution was evaporatedin vacuo. The residue was chromatographed on silica gel (12 g) elutingwith a mixture of methylene chloride and methanol (20:1-10:1) to give(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (314mg) as a crystalline solid.

EXAMPLE 100 ##STR121##

To a suspension of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one (735mg) in methylene chloride (30 ml) were added 2,2-dimethoxypropane (0.513ml) and boron trifluoride etherate (0.026 ml) at 0° C. The mixture wasstirred for 10 minutes at 0° C. and for 5 hours at ambient temperature.The reaction mixture was poured into a mixture of methylene chloride (30ml) and aqueous sodium bicarbonate and sodium chloride (1:1). Theorganic layer was separated and the aqueous layer was extracted withmethylene chloride (20 ml). The combined organic layers were washed withbrine, dried over magnesium sulfate, and evaporated in vacuo. Theresidue was chromatographed on silica gel (16 g) eluting with a mixtureof methylene chloride and acetone (10:1-5:1) to give(6R,7R)-7-benzyloxycarbonylamino-2,2-dimethyl-1-aza-3-oxabicyclo-[4.2.0]octan-8-one(753 mg) as an oil.

IR (CH₂ Cl₂): 1760, 1725 cm⁻¹.

NMR (acetone-d₆) δ: 1.36 (s, 3H), 1.61 (s, 3H), 1.4-2.1 (m, 2H), 3.5-3.9(m, 3H), 4.38 (dd, 1H, J=2, 8 Hz), 5.08 (s, 2H), 7.0 (broad, 1H), 7.35(s, 5H).

EXAMPLE 101 ##STR122##

A mixture of(6R,7R)-7-benzyloxycarbonylamino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one(748 mg) and 10% palladium charcoal (180 mg) in ethyl acetate (15 ml)was stirred under a hydrogen atmosphere for 1.5 hours at ambienttemperature. The mixture was filtered and the filtrate was evaporated invacuo to give(6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (382mg) as a crystalline solid.

IR (CH₂ Cl₂): 1740 cm⁻¹.

NMR (CDCl₃) δ: 1.42 (s, 3H), 1.72 (s, 3H), 1.5-2.1 (m, 2H), 1.86 (s,2H), 3.34 (ddd, 1H, J=2, 5, 10 Hz), 3.6-3.9 (m, 3H).

EXAMPLE 102 ##STR123##

To a solution of(6R,7R)-7-amino-2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (300mg) were added pyridine (0.25 ml) and freshly prepared acetic formicanhydride (0.38 ml) at 0° C. After stirring for 45 minutes at 0° C., thereaction mixture was evaporated in vacuo. The residue was dissolved inxylene and the solution was evaporated in vacuo. The residue waschromatographed on silica gel (6 g) eluting with a mixture of methylenechloride and methanol (25:1-10:1) to give(6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one(378 mg) as an oil.

IR (CH₂ Cl₂): 1755, 1685 cm⁻¹.

NMR (CDCl₃) δ: 1.43 (s, 3H), 1.72 (s, 3H), 1.8-2.1 (m, 2H), 3.56 (ddd,1H, J=2, 5, 10 Hz), 3.7-3.9 (m, 2H), 4.37 (dd, 1H, J=2, 8 Hz), 7.33(broad d, 1H, J=8 Hz), 8.11 (s, 1H).

EXAMPLE 103 ##STR124##

To a solution of(6R,7R)-2,2-dimethyl-7-formamido-1-aza-3-oxabicyclo[4.2.0]octan-8-one(345 mg) were added 2,6-lutidine (2.05 ml) and phosphorus oxychloride(0.52 ml) at 0° C. After stirring for 3 hours at 0° C., the mixture waspoured into a mixture of ethyl acetate (80 ml) and ice-water. Theorganic layer was separated, washed in turn with 10% phosphoric acid,water, brine, an aqueous mixture of sodium bicarbonate and sodiumchloride (1:1), and brine, dried over magnesium sulfate, and evaporatedin vacuo. The crystalline residue was washed with a mixture of petroleumether and ether (1:1) and dried over phosphorus pentoxide to give(6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(205 mg).

IR (CH₂ Cl₂): 2140, 1770 cm⁻¹.

NMR (CDCl₃) δ: 1.45 (s, 3H), 1.72 (s, 3H), 1.4-2.1 (m, 2H), 3.7-3.9 (m,3H), 4.30 (d, 1H, J=2 Hz).

EXAMPLE 104 ##STR125##

Ozone was passed into a solution of methyl2-{(3S,4R)-3-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl}-3-methylbut-2-enoate(100 mg) in methanol (3 ml) at -70° C. until a blue color was appeared.In the course of the reaction, white crystals were precipitated from thereaction mixture. After stirring for 10 minutes at -70° C., the mixturewas purged with nitrogen. Cold methylene chloride (2 ml) and dimethylsulfide (0.6 ml) were added to the mixture at -70° C. and the mixturewas warm to 0° C. during 1 hour. Then the mixture was left at 0° C. for3 hours and at ambient temperature for 12 hours. The mixture wasevaporated in vacuo and the residue was dissolved in methanol (5 ml).Dimethyl sulfide (0.3 ml), trimethyl orthoformate (0.5 ml) andp-toluenesulfonic acid monohydrate (4.3 mg) were added to the solutionand the mixture was heated for an hour at 58°-55° C. Pyridine (2 drops)was added to the mixture at ambient temperature and the mixture wasevaporated in vacuo. The residue was dissolved with ethyl acetate (30ml) and the solution was washed in turn with water, brine containing0.1N hydrochloric acid, brine, an aqueous saturated sodium bicarbonatecontaining sodium chloride, and brine, dried over magnesium sulfate, andevaporated in vacuo. The residue was dissolved in methanol (5 ml) andthe solution was left for 15 hours at ambient temperature. The mixturewas evaporated in vacuo and the residue was chromatographed on silicagel (2 g) eluting with a mixture of methylene chloride and acetone(20:1-5:1) to give(3S,4R)-4-(2,2-dimethoxyethyl)-3-[(1R)-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]azetidin-2-one(75 mg) as an oil.

IR (CH₂ Cl₂): 1760, 1730, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.44 (d, 3H, J=7 Hz), 1.94 (t, 2H, J=6 Hz), 3.03 (dd, 1H,J=2, 5 Hz), 3.32 (s, 6H), 3.70 (dt, 1H, J=2, 6 Hz), 4.43 (t, 1H, J=6Hz), 5.0-5.3 (m, 1H), 5.24 (s, 2H), 6.65 (s, 1H), 7.86 (A₂ B₂, 4H, J=9Hz).

EXAMPLE 105 ##STR126##

A mixture of(6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(150 mg), tributyltinhydride (0.263 ml), and azobisisobutyronitrile (14mg) in benzene (4.5 ml) was refluxed for 15 minutes. The resultingsolution was chromatographed on silica gel (4.5 g) eluting with amixture of benzene and acetone (15:1-16:1) to give the crude product(140 mg) as an oil, which was purified by silica gel (5 g)chromatography (eluate: a mixture of methylene chloride and ethylacetate 30:1-5:1) to give(6R)-2,2-dimethyl-1-aza-3-oxabicycle[4.2.0]-octan-8-one (98 mg) as anoil.

IR (CH₂ Cl₂): 1740 cm⁻¹.

NMR (CDCl₃) δ: 1.42 (s, 3H), 1.77 (s, 3H), 1.4-2.1 (m, 2H), 2.56 (dd,1H, J=2.5, 14.5 Hz), 3.08 (dd, 1H, J=5, 14.5 Hz), 3.5-3.7 (m, 1H), 3.87(dd, 2H, J=2.5, 8 Hz).

EXAMPLE 106 ##STR127##

To a solution of(6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicycle[4.2.0]octan-8-one(200 mg) in tetrahydrofuran (4 ml) was added a solution ofn-butyllithium in hexane (0.93 ml of 1.55M solution) at -70° C. and themixture was stirred at -70° C. for 15 minutes. A solution ofacetaldehyde (73 mg) in tetrahydrofuran (0.8 ml) was added to themixture at -70° C. and the mixture was stirred at -70° C. for 30minutes. Acetic acid (0.19 ml) was added to the mixture at -70° C. andthe mixture was poured into a mixture of ethyl acetate (100 ml) andaqueous sodium bicarbonate containing a small amount of sodium chloride.The aqueous layer was separated and extracted with ethyl acetate (20ml). The combined organic layers were washed with brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue waschromatographed on silica gel (3 g) eluting with a mixture methylenechloride and ethyl acetate (20:1-5:1) to give a mixture of(6R,7R)-2,2-dimethyl-7-[(1S)-1-hydroxyethyl]-7-isocyano-1-aza-3-oxabicycle[4.2.0]octan-8-one,its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (1S,6R,7S) isomeras a solid (230 mg).

IR (CH₂ Cl₂): 3600, 2140, 1770 cm⁻¹.

NMR (CDCl₃) δ: 1.3-1.6 (m, 3H), 1.44 (s, 3H), 1.76 (s, 3H), 1.6-2.2 (m,3H), 2.8-3.1 (m, 1H), 3.7-4.1 (m, 2H), 4.0-4.4 (m, 1H).

EXAMPLE 107 ##STR128##

To a mixture of(6R,7R)-2,2-dimethyl-7-[(1S)-1-hydroxyethyl]-7-isocyano-1-aza-3-oxabicycle[4.2.0]-octan-8-one,its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (1S,6R,7S) isomer(210 mg) in benzene (10 ml) were added tributyltinhydride (0.297 ml) andazobisisobutyronitrile (15 mg) at ambient temperature and the mixturewas refluxed for 30 minutes. The resulting solution weas chromatographedon silica gel (7.5 g) eluting with a mixture of methylene chloride andacetone (10:1-5:1) to give the crude product, which was purified bysilica gel (10 g) chromatography (a mixture of hexane and ethyl acetate5:1-1:5) to give a mixture of(6R,7R)-2,2-dimethyl-7-[(1S)-1-hydroxyethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one,its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (1S,6R,7S) isomeras an oil (157 mg).

IR (CH₂ Cl₂): 3400, 1740 cm⁻¹.

NMR (CDCl₃) δ: 1.1-1.4 (m, 3H), 1.43 (2,3H), 1.76 (s, 3H), 1.6-2.2 (m,3H), 2.2-3.0 (m, 1H), 3.0-3.2 (m, 1H), 3.6-4.0 (m, 2H), 4.0-4.4 (m, 1H).

EXAMPLE 108 ##STR129##

A solution of p-nitrobenzyl chloroformate (251 mg) in methylene chloride(2.5 ml) was added to a mixture of(6R,7R)-2,2-dimethyl-7-[(1S)-1-hydroxyethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one,its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, its (1S,6R,7S) isomer, and4-(dimethylamino)pyridine (143 mg) in methylene chloride (3 ml) at 0° C.After stirring at 0° C. for 30 minutes, the mixture was allowed to warmto ambient temperature during 45 minutes and stirred at ambienttemperature for 1.5 hours. A solution of p-nitrobenzyl chloroformate(100 mg) in methylene chloride (1 ml) and 4-(dimethylamino)pyridine (58mg) were added to the mixture at 0° C. and the mixture was stirred atambient temperature for 1.5 hours.

3-Dimethylaminopropylamine (0.158 ml) was added to the mixture at 0° C.and the mixture was stirred at 0° C. for 15 minutes. The mixture waspoured into a mixture of ethyl acetate (70 ml) and dilute hydrochloricacid. The organic layer was separated, washed with brine, aqueous sodiumbicarbonate, and brine, dried over magnesium sulfate, and evaporated invacuo. The residue was chromatographed on silica gel (10 g) eluting witha mixture of methylene chloride and ethyl acetate (10:1-2:1) to give a9:11:4:1 mixture of(6R,7R)-2,2-dimethyl-7-[(1S)-1-(4-nitrobenzyloxycarbonyoxy)ethyl]-1-aza-3-oxabicyclo-[4.2.0]octan-8-one,its (1R,6R,7R) isomer, its (1R,6R,7S) isomer, and its (1S,6R,7S) isomeras an oil (167 mg).

The residue was chromatographed on silica gel (15 g) eluting with amixture of cyclohexane and ethyl acetate (5:1→1:1) to give 70 mg of the(1S,6R,7R)-isomer and 60 mg of the (1R,6R,7R)-isomer, and 10 mg of the(1R,6R,7S)-isomers.

Deta for the (1S,6R,7R)-isomer: IR (CH₂ Cl)₂ : 1745, 1525, 1350 cm⁻¹ ;NMR (CDCl₃) δ: 1.2-2.0 (m, 2H), 1.50 (d, 3H, J=6 Hz), 1.74 (s, 3H), 3.42(dd, 1H, J=5, 11 Hz), 3.6-4.0 (m, 1H), 5.22 (dq, 1H, J=11, 6 Hz), 5.30(s, 2H), 7.94 (A₂ B₂, 4H, J=9 Hz).

Deta for the (1R,6R,7R)-isomer: IR (CH₂ Cl₂): 1745, 1525, 1350 cm⁻¹ ;NMR (CDCl₃) δ: 1.3-2.0 (m, 2H), 1.4 (d, 3H, partially hidden), 1.44 (s,3H), 1.75 (s, 3H), 3.39 (dd, 1H, J=5.5, 9 Hz), 3.7-4.1 (m, 3H), 5.1-5.4(m, 1H), 5.34 (s, 2H), 7.98 (A₂ B₂, 4H, J=9 Hz).

Date for the (1R,6R,7S)-isomer: IR (CH₂ Cl₂): 1745, 1525, 1350 cm⁻¹ ;NMR (CDCl₃) δ: 1.3-2.0 (m, 2H), 1.42 (s, 3H), 1.47 (d, 3H, J=6 Hz), 1.76(s, 3H), 3.00 (dd, 1H, J=2, 8 Hz), 3.5-4.0 (m, 3H), 5.1 (m, 1H), 5.30(s, 2H), 7.96 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 109 ##STR130##

To a solution of(6R,7R)-2,2-dimethyl-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(500 mg) in tetrahydrofuran (15 ml) was added a solution ofn-butyllithium in hexane (2.33 ml of 1.55M solution) at -70° C. and themixture was stirred at -70° C. for 15 minutes. A solution of acetone(0.265 ml) in tetrahydrofuran (2.4 ml) was added to the reaction mixtureat -70° C. and the mixture was stirred at -70° C. for 25 minutes. Aceticacid (0.477 ml) was added to the mixture at -70° C. After stirring at-70° C. for 20 minutes, the mixture was evaporated in vacuo. The residuewas dissolved in ethyl acetate (80 ml) and the solution was washed withaqueous sodium bicarbonate. The aqueous layer was separated andextracted with ethyl acetate (20 ml). The combined organic layers werewashed with brine, dried over magnesium sulfate, and evaporated invacuo. The crystalline residue was washed with isopropyl ether andfiltered to give(6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(460 mg).

The mother liquor was chromatographed on silica gel (5 g) eluting with amixture of hexane and ethyl acetate (20:1-1:1) to give additional(6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(65 mg) [(6R,7R)-isomer] and its (6R,7S)-isomer (103 mg).

For (6R,7R)-isomer: IR (CH₂ Cl₂): 2125, 1765 cm⁻¹. NMR (CDCL₃) δ: 1.38(s, 3H), 1.43 (s, 3H), 1.50 (s, 3H), 1.74 (s, 3H), 1.5-2.2 (m, 2H), 2.10(s, 1H), 3.7-4.0 (m, 3H).

For (6R,7S)-isomer: IR (CH₂ Cl₂): 2125, 1765 cm⁻¹. NMR (CDCl₃) δ: 1.40(s, 3H), 1.48 (s, 3H), 1.63 (s, 3H), 1.74 (s, 3H), 1.5-1.9 (m, 1H), 2.21(s, 1H), 2.6-3.0 (m, 1H), 3.7-4.0 (m, 3H).

EXAMPLE 110 ##STR131##

To a mixture of(6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-oneand its (6R,7S)-isomer (2.5 g) in benzene (75 ml) were addedtributyltinhydride (3.07 ml) and azobisisobutyronitrile (170 mg) atambient temperature and the mixture was refluxed for 30 minutes. Thereaction mixture was chromatographed on silica gel (65 g) eluting with amixture of methylene chloride and acetone (10:1-2:1) to give a crudeproduct, which was purified by silica gel (75 g) chromatography (hexaneand ethyl acetate) to give(6R,7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4,2,0]-octan-8-one(0.545 g) [(6R,7S)-isomer] and its (6R,7R)-isomer (1.406 g).

For (6R,7S)-isomer: IR (CH₂ Cl₂): 1735 cm⁻¹. NMR (CDCl₃) δ: 1.29 (s,3H), 1.36 (s, 3H), 1.42 (s, 3H), 1.74 (s, 3H), 1.5-2.0 (m, 2H), 1.96 (s,1H), 2.81 (d, 1H, J=2 Hz), 3.52 (ddd, 1H, J=2, 5.5, 11 Hz), 3.83 (dd,2H, J=3, 8.5 Hz).

For (6R,7R)-isomer: IR (CH₂ Cl₂): 1735 cm⁻¹. NMR (CDCl₃) δ: 1.28 (s,3H), 1.40 (s, 3H), 1.47 (s, 3H), 1.74 (s, 3H), 1.5-2.0 (m, 1H), 1.98 (s,1H), 2.5-2.9 (m, 1H), 3.15 (d, 1H, J=5 Hz), 3.6-3.9 (m, 3H).

In the same manner described above,(6R,7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]octan-8-one(50 mg) afforded a 2:5 mixture of(6R,7S)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-oneand its (6R,7R)-isomer (40 mg).

EXAMPLE 111 ##STR132##

To a solution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(127.6 mg) in tetrahydrofuran (2.55 ml) was added dropwise a solution ofn-butyl lithium (0.409 ml of 1.51M solution in hexane) at -78° C. over aperiod of 3 minutes. After stirring for 15 minutes at -78° C., thereaction mixture was added dropwise with a solution of acetone (0.0459ml) in tetrahydrofuran (0.459 ml) at -78° C. over a period of 3 minutes.After stirring for 25 minutes at -78° C., the reaction mixture was addeddropwise with a solution of 4-nitrobenzyl chloroformate (124.1 mg) intetrahydrofuran (1.24 ml) at -78° C. over a period of 3 minutes. Theresulting solution was allowed to warm to 0° C. over a period of 40minutes and added with acetic acid (0.0412 ml) at 0° C. The solvent wasdistilled off in vacuo at 0° C. and the residue was dissolved in ethylacetate (30 ml) and washed with brine, aqueous sodium bicarbonate, brineand saturated aqueous sodium chloride. After drying over magnesiumsulfate, the ethyl acetate extract was filtered and evaporated in vacuo.The residual oil (285.4 mg) was chromatographed on silica gel (5.7 g)eluting with a mixture of ethyl acetate and hexane (1:5→1:3) to givemethyl2-{(3R,4R)-3-isocyano-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl}-3-methylbut-2-enoate(211.2 mg) as an oil.

IR (CH₂ Cl₂): 2130, 1775, 1750, 1720, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.74 (s, 3H), 1.83 (s, 3H), 1.97 (s, 3H), 2.22 (s, 3H),2.53 (t, 2H, J=7 Hz), 3.71 (s, 3H), 4.32 (t, 1H, J=7 Hz), 5.0-5.3 (m,4H), 5.5-5.9 (m, 1H), 7.84 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 112 ##STR133##

To a solution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(198.0 mg) in tetrahydrofuran (3.96 ml) was added dropwise a solution ofn-butyl lithium (0.634 ml of 1.51M solution in hexane) at -78° C. over aperiod of 5 minutes. After stirring for 15 minutes at -78° C., thereaction mixture was added with a solution of acetone (0.0713 ml) intetrahydrofuran (0.642 ml) at -78° C. over a period of 5 minutes. Afterstirring for 25 minutes at -78° C., the reaction mixture was addeddropwise with a solution of benzyl chloroformate (0.1274 ml) intetrahydrofuran (1.15 ml) at -78° C. over a period of 5 minutes. Theresulting solution was allowed to warm to 0° C. over a period of 40minutes and added with acetic acid (0.0639 ml) at 0° C. The solvent wasdistilled off in vacuo at 0° C. and the residue was dissolved in ethylacetate (30 ml) and washed with brine, aqueous sodium bicarbonate,brine, and saturated aqueous sodium chloride. After drying overmagnesium sulfate, the ethyl acetate extract was filtered and evaporatedin vacuo. The residual oil (381.2 mg) was chromatographed on silica gel(11 g) eluting with a mixture of ethyl acetate and hexane (1:10→1:5) togive methyl2-[(3R,4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(221.2 mg) as an oil.

IR (CH₂ Cl₂): 2130, 1770, 1745, 1720 cm⁻¹.

NMR (CDCl₃) δ: 1.71 (s, 3H), 1.85 (s, 3H), 1.95 (s, 3H), 2.20 (s, 3H),2.53 (t, 2H, J=7 Hz), 3.63 (s, 3H), 4.35 (t, 1H, J=7 Hz), 5.0-5.35 (m,4H), 5.5-6.0 (m, 1H), 7.3-7.5 (m, 5H).

EXAMPLE 113 ##STR134##

A mixture of methyl2-[(3R,4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-3-isocyano-2-oxo-4-allylazetidin-yl]-3-methylbut-2-enoate(42.7 mg), tri-n-butyltinhydride (0.0308 ml) and azobisisobutyronitrile(0.622 mg) in benzene (2.14 ml) was refluxed for 30 minutes. Theresulting solution was chromatographed on silica gel (2.1 g) elutingwith a mixture of ethyl acetate and hexane (1:10→1:2) to give a mixtureof methyl2-[(3R,4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoateand methyl2-[(3S,4R)-3-(1-benzyloxycarbonyloxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(39.8 mg; ratio=1:2.3) as an oil.

IR (CH₂ Cl₂): 1750, 1740, 1730 cm⁻¹.

NMR (CDCl₃) δ: 1.59 (s, 2.1H), 1.61 (s, 0.9H), 1.65 (s, 2.1H), 1.67 (s,0.9H), 1.75 (s, 0.9H), 1.91 (s, 2.1H), 1.96 (s, 0.9H), 2.18 (s, 2.1H),2.31 (t, 1.4H, J=7 Hz), 2.61 (t, 0.6H, J=7 Hz), 3.42 (d, 0.7H, J=2 Hz),3.5-3.8 (m, 3.3H), 3.88-4.22 (m, 1H), 4.8-5.2 (m, 4H), 5.3-5.9 (m, 1H),7.0-7.5 (m, 5H).

EXAMPLE 114 ##STR135##

To a solution of methyl2-{(3S,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allyl-azetidin-1-yl}-3-methylbut-2-enoate(72.9 mg) in acetone (2.03 ml) was added a 0.7M solution of phosphatebutter (pH 6.8, 1.35 ml) at ambient temperature. To the resultingsuspension was added dropwise a solution of sodium periodate (86.0 mg)in water (0.594 ml) at ambient temperature. After stirring for 10minutes, the reaction mixture was added with sodium periodate (117.2 mg)and potassium permanganate (37.5 mg) and stirred at ambient temperatureovernight. The resulting mixture was diluted with water-acetone (15ml-15 ml) and filtered with celite and the filter cake was washed withwater-acetone (1:1). The combined filtrates were concentrated in vacuoat 0° C., acidified to pH 1 with 10% aqueous phosphoric acid, andextracted with chloroform. The organic layer was extracted with chilled10% aqueous sodium bicarbonate (X3). The aqueous extracts were acidifiedwith 3N hydrochloric acid and reextracted with chloroform (X3). Thechloroform extracts were washed with saturated aqueous sodium chloridecontaining a small amount of 3N hydrochloric acid, dried over magnesiumsulfate, filtered, and evaporated to give{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}aceticacid (36.4 mg) as an amorphous solid.

IR (CH₂ Cl₂): 1740, 1520, 1350 cm⁻¹.

EXAMPLE 115 ##STR136##

n-Butyllithium (1.51N in hexane, 0.99 ml) was added dropwise to asolution of methyl2-[(3R,4R)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(308 mg) in tetrahydrofurane (6 ml) during a three-minutes period at-78° C. under a nitrogen atmosphere. After 15 minutes at -78° C. asolution of acetaldehyde in tetrahydrofuran (2M, 0.93 ml) was addeddropwise. The mixture was stirred at -78° C. for 30 minutes and quenchedby addition of acetic acid (143 μl). The solution was allowed to warm to0° C., poured into a mixture of a saturated aqueous solution of sodiumbicarbonate and brine, and extracted with ethyl acetate (50 ml). Theextract was washed with brine, dried over magnesium sulfate andevaporated to give an oil (274 mg). The residue was chromatographed onsilica gel (5 g; eluting with 5-10% acetone in dichloromethane) to give199 mg (54.9%) of four diastereomeric mixture of methyl2-[(4R)-3-(1-hydroxyethyl)-3-isocyano-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate.

IR (CH₂ Cl₂): 3450, 2140, 1770, 1725 cm⁻¹.

EXAMPLE 116 ##STR137##

Tri(n-butyl)tin hydride (0.20 ml) and azobisisobutyronitrile (11.5 mg)were added to a solution of the four isomeric mixture of methyl2-[3-(1-hydroxyethyl)-3-isocyano-2-oxo-4(R)allylazetidin-1-yl]-3-methylbut-2-enoate(195 mg) in anhydrous benzene (4 ml). The stirring mixture was heated toreflux for 15 minutes. The reaction mixture was cooled to ambienttemperature and chromatographed on silica gel (6 g; eluting with amixture of 5-20% acetone in dichloromethane to give 155 mg (87.3%) ofthe four-isomeric mixture of methyl2-[(4R)-3-(1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoateas a crude oil. This crude oil (118 mg) was chromatographed on silicagel (10 g; eluting with 4-20% acetone in benzene) to give 47 mg ofmethyl2-[(3S,4R)-3-((1RS)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoateand 54 mg of methyl2-[(3R,4R)-3-((1RS)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate.

IR (CH₂ Cl₂) for the mixture of four isomers, 3640, 3550, 3100-3600,1735, and 1715 cm⁻¹.

EXAMPLE 117 ##STR138##

A solution of 4-nitrobenzyl chloroformate (64.7 mg) in dichloromethane(0.65 ml) was added to a solution of methyl2-[(3S,4R)-3-((1RS)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate(54 mg) and dimethylaminopyridine (36.7 mg) in dichloromethane (2.35 ml)at 0° C. under a nitrogen atmosphere. After three minutes theheterogeneous mixture was allowed to warm to ambient temperature (27°C.). After two hours-stirring, additional 4-nitrobenzyl chloroformate(43 mg) and dimethylaminopyridine (25 mg) were added at 0° C. Themixture was stirred at ambient temperature for 15 hours and theresulting solution was evaporated. The residue was taken up into ethylacetate (20 ml), washed in turn with dilute hydrochloric acid, water, adilute aqueous solution of sodium bicarbonate, and brine dried overmagnesium sulfate, and evaporated. The residue was chromatographed onsilica gel (2.5 g; eluting with 2% acetone in dichloromethane) to give76 mg (84.3%) of a 4:7 mixture of methyl2-[(3S,4R)-3-[(1RS)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoate.

IR (CH₂ Cl₂): 1750, 1720, 1525, and 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.46 (d, J=7 Hz, 1.2H), 1.48 (d, J=7 Hz, 1.8H), 1.97 (s,3H), 2.20 (s, 3H), 2.4 (m, 2H), 3.06 (dd, J=3, 8 Hz, 0.4H), 3.19 (dd,J=3, 5 Hz, 0.6H), 3.76 (s, 3H), 3.92 (m, 1H), 4.9-5.4 (m, 3H), 5.28 (s,2H), 5.5-6.0 (m, 1H), 7.56 (d, J=9 Hz, 0.8H), 7.58 (d, J=9 Hz, 1.2H),and 8.23 (d, J=9 Hz, 2H).

EXAMPLE 118 ##STR139##

In a manner similar to the Example 117, except using five molar excessof reagents, 47.0 mg of methyl2-[(3R,4R)-3-((1RS)-1-hydroxyethyl)-2-oxo-4-allylazetidin-1-yl]-3-methylbut-2-enoateafforded 64 mg (81.5%) of a 3:7 mixture of methyl2-{(3R,4R)-3-[(1RS)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-allylazetidin-1-yl}-3-methylbut-2-enoateand 7 mg (15%) of the starting material.

This mixture (60 mg) was chromatographed on a silica gel plate (20 cm×20cm×2 mm, three developments with a mixture of 6:4 hexane-ethyl acetate)to give 39 mg of the 1S isomer and 20 mg of the 1R isomer.

Deta for the 1S isomer: IR (CH₂ Cl₂): 1745, 1720, 1525, 1350 cm⁻¹. NMR(CDCl₃) δ: 1.57 (d, J=6 Hz, 3H), 1.94 (s, 3H), 2.20 (s, 3H), 2.40 (t,J=7 Hz, 2H), 3.51 (dd, J=5.5 and 11 Hz, 1H), 3.74 (s, 3H), 4.14 (dt,J=5.5 and 7 Hz), 4.9-5.3 (m, 3H), 5.27 (s, 2H), 5.4-5.9 (m, 1H), 7.57(d, J=9 Hz, 2H), and 8.25 (d, J=9 Hz, 2H) ppm.

Deta for the 1R isomer: IR (CH₂ Cl₂): 1745, 1720, 1525, 1350 cm⁻¹. NMR(CDCl₃) δ: 1.53 (d, J=6 Hz, 3H), 2.03 (s, 3H), 2.22 (s, 3H), 2.40 (t,J=7 Hz, 2H), 3.39 (dd, J=4 and 6 Hz, 1H), 3.76 (s, 3H), 4.13 (dt, J=6and 7 Hz, 1H), 4.7-5.3 (m, 3H), 5.30 (s, 2H), 5.4-5.9 (m, 1H), 7.56 (d,J=9 Hz, 2H), and 8.25 (d, J=9 Hz, 2H) ppm.

EXAMPLE 119 ##STR140##

To a solution of(6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]-octan-8-one(600 mg) in tetrahydrofuran (24 ml) was added a solution ofn-butyllithium (2.36 ml of 1.55M solution in hexane) at =70° C. and themixture was stirred at -70° C. for 15 minutes.

A solution of 4-nitrobenzyl chloroformate (788 mg) in tetrahydrofuran (7ml) was added to the mixture at -70° C. After stirring at -70° C. for 15minutes, the reaction mixture was allowed to warm to 0° C. during 50minutes, stirred at 0° C. for 30 minutes, and evaporated in vacuo. Theresidue was dissolved in ethyl acetate (100 ml) and the solution waswashed with aqueous sodium bicarbonate. The aqueous layer was separatedand extracted with ethyl acetate (20 ml). The combined organic layerswere washed with aqueous saturated sodium chloride, dried over magnesiumsulfate, and evaporated in vacuo. The residue was chromatographed onsilica gel (40 g) eluting with a mixture of hexane and ethyl acetate(10:1 to 1:1) to give a crystalline residue. The residue was washed withisopropyl ether and filtered to give(6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo-[4.2.0]octan-8-one(520 mg).

IR (CH₂ Cl₂): 1740, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.41 (s, 3H), 1.62 (s, 3H), 1.77 (s, 6H), 1.5-1.9 (m,1H), 2.2-2.5 (m, 1H), 3.42 (d, 1H, J=5.5 Hz), 3.6-4.0 (m, 3H), 5.20 (s,2H), 7.88 (A₂ B₂, 4H, J=9 Hz).

EXAMPLE 120 ##STR141##

A solution of(6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one(200 mg) in a mixture of acetic acid (3.2 ml) and water (0.8 ml) washeated at 65° C. for 1 hour. The mixture was cooled to room temperatureand evaporated in vacuo. The crystalline residue was washed with etherto give(3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one(151 mg).

IR (CH₂ Cl₂): 3575, 3375, 1750, 1520, 1350 cm⁻¹.

NMR (DMSO-d₆) δ: 1.57 (s, 3H), 1.64 (s, 3H), 1.88 (q, 2H, J=7 Hz),3.1-3.6 (m, 3H), 3.6-3.9 (m, 1H), 4.47 (t, 1H, J=5 Hz), 5.23 (s, 2H),7.90 (A₂ B₂, 4H, J=9 Hz), 8.08 (s, 1H).

EXAMPLE 121 ##STR142##

To a solution of(3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one(10 mg) in acetone (0.6 ml) was added 2N Jones reagent (50 μl) at 0° C.and the mixture was stirred at 0° C. for 20 minutes. Isopropyl alcohol(100 μl) was added to the mixture at 0° C. and the mixture wasevaporated in vacuo. The residue was dissolved in chloroform (10 ml) andthe solution was washed with brine. The aqueous layer was separated andextracted with chloroform (5 ml). The conbined organic layers werewashed with aqueous saturated sodium chloride, dried over magnesiumsulfate, and evaporated in vacuo. The residue was chromatographed onsilica gel (0.5 g) eluting with a mixture of methylene chloride andmethanol (20:1 to 5:1) to give pure{(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}aceticacid (3 mg) and impure material (5 mg).

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 122 ##STR143##

To a solution of[(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl]-aceticacid (56.4 mg) in tetrahydrofuran (1.13 ml) was addedN,N-carbonyldiimidazole (27.5 mg) at ambient temperature. After stirringfor 6 hours at ambient temperature, the magnesium salts of themono-p-nitrobenzyl ester of malonic acid (84.8 mg) was added and theresulting mixture was stirred overnight at ambient temperature. Thesolvent was distilled off and the residue was dissolved in ethyl acetate(30 ml) and filtered with a diatomaceous earth. The filtrate was washedwith 1N hydrochloric acid, water, phosphate butter solution (pH 6.8),and saturated aqueous sodium chloride. After drying over magnesiumsulfate, the ethyl acetate extract was filtered and evaporated in vacuo.The residual oil (78.8 mg) was chromatographed on silica gel (1.6 g)eluting with a mixture of methylene chloride and ethyl acetate (10:1 to2:1) to give 4-nitrobenzyl4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (64.2 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3380, 1760, 1740, 1720, 1520, 1340 cm⁻¹.

NMR (CDCl₃) δ: 1.62 (s, 3H), 1.66 (s, 3H), 2.86-3.12 (m, 2H), 3.41 (d,1H, J=2 Hz), 3.65 (s, 2H), 3.94-4.18 (m, 1H), 5.25 (s, 2H), 5.34 (s,2H), 6.60 (broad s, 1H), 7.63 (d, 4H, J=9 Hz), 8.30 (d, 4H, J=9 Hz).

EXAMPLE 123 ##STR144##

To a solution of 4-nitrobenzyl4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate(58.3 mg) in acetonitrile (1.17 ml) was added a solution ofp-toluenesulfonyl azide (25.3 mg) in acetonitrile (0.228 ml) at 0° C.After stirring for 5 minutes at 0° C., a solution of triethylamine (53.7μl) in acetonitrile (0.483 ml) was added dropwise. The stirring mixturewas allowed to warm to ambient temperature during 15 minutes and kept atthe same temperature for 20 minutes. The solvent was distilled off andthe residue (85.9 mg) was flash chromatographed on silica gel (1 g)eluting with a mixture of methylene chloride and ethyl acetate (50:1 to3:1) to give 4-nitrobenzyl2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate(58.4 mg) as an amorphous solid

IR (CH₂ Cl₂): 3380, 2140, 1760, 1740, 1715, 1645, 1520, 1345 cm⁻¹.

NMR (CDCl₃) δ: 1.63 (s, 3H), 1.67 (s, 3H), 2.88-3.34 (m, 2H), 3.46 (d,1H, J=2 Hz), 3.90-4.20 (m, 1H), 5.26 (s, 2H), 5.45 (s, 2H), 6.48 (broads, 1H), 7.65 (d, 4H, J=9 Hz), 8.30 (d, 2H, J=9 Hz), 8.34 (d, 2H, J=9Hz).

EXAMPLE 124 ##STR145##

A mixture of 4-nitrobenzyl2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate(58.0 mg) and rhodium (II) acetate (0.1 mg) in benzene (3.4 ml) wasrefluxed for 30 minutes. After cooling to ambient temperature, themixture was filtered with a diatomaceous earth and evaporated to give4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]-heptane-2-carboxylate(47.8 mg) as an amorphous solid.

IR (CH₂ Cl₂): 1760, 1735, 1730, 1515, 1345 cm⁻¹.

NMR (CDCl₃) δ: 1.70 (s, 3H), 2.49 (AB part of ABX system centered at2.49, 2H, JAB=18 Hz, JAX=JBX=7 Hz), 3.78 (d, 1H, J=2 Hz), 4.21 (dt, 1H,J=2, 7 Hz), 4.79 (s, 1H), 5.21 (s, 2H), 5.30 (ABq, 1H, J=12 Hz), 7.53(d, 2H, J=9 Hz), 8.22 (d, 2H, J=9 Hz).

EXAMPLE 125 ##STR146##

To a solution of4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate(47.8 mg) and 4-(N,N-dimethylamino)pyridine (1.08 mg) in acetonitrile(2.39 ml) was added dropwise a solution of di-isopropylethylamine (18.5μl) in acetonitrile (166.5 μl) followed by addition of a solution ofdiphenyl chlorophosphate (19.2 μl) in acetonitrile (172.8 μl) at 0° C.After stirring for an hour at 0° C., a solution ofdi-isopropylethylamine (61.5 μl) in acetonitrile (553.5 μl) was addedfollowed by addition of a solution of N-(2-mercaptoethyl)-acetamide(11.05 mg) in acetonitrile (99.45 μl) at -15° C. The mixture was allowedto stand overnight at -15° C. The resulting solution was diluted withethyl acetate (34 ml) and washed with dilute aqueous sodium chloride andsaturated aqueous sodium chloride. After drying over magnesium sulfate,the ethyl acetate extract was filtered and evaporated in vacuo. Theresidual oil (76.4 mg) was chromatographed on silica gel (1.5 g) elutingwith a mixture of methylene chloride and acetone (20:1 to 2:1) to give4-nitrobenzyl(5R,6S)-3-(2-acetamido-ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate(54.0 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3410, 1775, 1725, 1710, 1685, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.65 (s, 6H), 1.98 (s, 3H), 2.7-3.6 (m, 6H), 3.77 (d, 1H,J=3 Hz), 4.27 (dt, 1H, J=3, 8 Hz), 5.18 (s, 2H), 5.33 (ABq centered at5.33, 2H, J=13 Hz), 6.21 (broad s, 1H), 7.50 (d, 2H, J=9 Hz), 7.58 (d,2H, J=9 Hz), 8.14 (d, 2H, J=9 Hz), 8.16 (d, 2H, J=9 Hz).

EXAMPLE 126 ##STR147##

A mixture of 5% palladium-charcoal (40.0 mg), water (0.96 ml) anddioxane (2.24 ml) was shaken for 30 minutes under hydrogen atmosphere(40 psi) at ambient temperature. The mixture was added to a solution of4-nitrobenzyl(5R,6S)-3-(2-acetamido-ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(40.0 mg) in a mixture of water (0.24 ml) and dioxane (0.56 ml), andshaken for 2 hours under hydrogen atmosphere (40 psi) at ambienttemperature. The resulting mixture was added with 1% aqueous sodiumhydrogen carbonate (0.522 ml) at 0° C. and filtered by usingdiatomaceous earth. The filtered cake was washed with water (3×5 ml) andthe combined filtrates were concentrated, washed with ethyl acetate(3×20 ml) and evaporated in vacuo. The residue was dissolved in water(25 ml) containing sodium chloride (0.7 g) and chromatographed on a nonionic adsorption resin HP-20 (trademark, made by Mitsubishi ChemicalIndustries) (1.0×20 cm) eluting with a mixture of water and acetone(100:0 to 7:3, 200 ml). The fractions containing the product werecombined and lyophilized to give sodium(5R,6S)-3-(2-acetamido-ethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(6.9 mg) as a white solid.

IR (CH₂ Cl₂): 3310, 1745, 1655, 1600, 1555, 1400 cm⁻¹. UV (in H₂ O): 301nm.

EXAMPLE 127 ##STR148##

A solution of(3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one(10 mg) in dichloromethane (1.5 ml) was added to a suspension ofpyridinium chlorochromate (9.2 mg) in dichloromethane at 0° C. Thestirring mixture was allowed to warm to ambient temperature and kept atthe same temperature for 1.5 hours. The reaction mixture was poured intoa mixture of dichloromethane (20 ml) and dilute hydrochloric acid. Theorganic layer was separated and washed in turn with brine, diluteaqueous solution of sodium bicarbonate containing sodium thiosulfate,and brine. The organic layer was dried over magnesium sulfate andevaporated to give a crystalline solid (12 mg). A silica gelchromatography (0.5 g) eluting with a mixture of dichloromethane andacetone (10:1 to 5:1) afforded(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one(9.7 mg) as a crystalline solid.

IR (CH₂ Cl₂): 3375, 1760, 1750 (shoulder), 1715, 1520, 1350 cm⁻¹.

EXAMPLE 128 ##STR149##

To a solution of(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one(9 mg) in acetone (1 ml) was added 2N Jones reagent (60 μl) at 0° C. andthe mixture was stirred at 0° C. for 30 minutes. After addition ofisopropyl alcohol (100 μl), the mixture was evaporated in vacuo. Theresidue was taken up in chloroform (20 ml) and washed with brine. Theaqueous layer was extracted with chloroform (5 ml). The combined organiclayers were washed with aqueous saturated sodium chloride, dried overmagnesium sulfate, and evaporated to give{(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl}aceticacid (7 mg).

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 129 ##STR150##

Methyl3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate andits (3S,4R)-isomer were prepared from methyl3-methyl-2-[(3R,4R)-4-chloro-3-methyl-2-oxo-azetidin-1-yl]but-2-enoateand its (3S,4R)-isomer in a similar manner to that of Example 7.

For the (3R,4R)-isomer:

IR (CH₂ Cl₂): 1740, 1710 cm⁻¹. NMR (CDCl₃) δ: 1.32 (d, 3H, J=7.5 Hz),1.93 (s, 1H), 1.19 (s, 1H), 2.36 (q, 2H, J=8 Hz), 2.84 (dq, 1H, J=2.5,7.5 Hz), 3.56 (dt, 1H, J=2.5, 8 Hz), 3.72 (s, 3H), 4.9-6.3 (m, 2H),5.5-6.0 (m, 1H).

For the (3S,4R)-isomer:

IR (CH₂ Cl₂): 1740, 1715 cm⁻¹. NMR (CDCl₃) δ: 1.23 (d, 3H, J=8 Hz), 1.95(s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz), 3.36 (dq, 1H, J=6, 8 Hz),3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.4-5.9 (m,2H).

EXAMPLE 130 ##STR151##

To a solution of4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate(148.5 mg) and 4-N,N-dimethylaminopyridine (3.35 mg) in acetonitrile(7.4 ml) was added dropwise a solution of di-isopropylethylamine (57.3μl) in acetonitrile (0.516 ml). To the mixture was further added asolution of diphenyl chlorophosphate (59.6 μl) in acetonitrile (0.536ml) at 0° C. After stirring for an hour at 0° C., a solution ofdiisopropylethylamine (190.9 μl) in acetonitrile (1.72 ml) was added tothe mixture. To the mixture was further added a solution ofN-(4-nitrobenzyloxycarbonyl)cysteamine (73.8 mg) in acetonitrile (0.664ml) at -15° C. The mixture was allowed to stand overnight at -15° C. Theresulting solution was diluted with ethyl acetate (15 ml) and washed inturn with water and saturated aqueous sodium chloride. After drying overmagnesium sulfate, the ethyl acetate extract was filtered and evaporatedin vacuo. The residue was chromatographed on silica gel (3 g) elutingwith a mixture of methylene chloride and ethyl acetate (50:1 to 5:1) togive4-nitrobenzyl(5R,6S)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(167.8 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3390, 1775, 1730, 1725, 1610, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.62 (6H, s), 2.80-3.60 (6H, m), 3.78 (1H, d, J=3.0 Hz),4.29 (1H, dt, J=3,8 Hz), 5.17 (2H, s), 5.34 (4H, ABq, J=14 Hz),7.30-7.80 (6H, m), 8.05-8.30 (6H, m).

EXAMPLE 131 ##STR152##

To a solution of4-nitrobenzyl(5R,6S)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(17.6 mg) in methylene chloride (0.70 ml) was added dropwise a solutionof m-chloroperbenzoic acid (6.50 mg) in methylene chloride (0.319 ml)over a period of 5 minutes at -20° C. After stirring for 30 minutes at-20° C., the reaction mixture was diluted with ethyl acetate (10 ml),washed in turn with chilled 10% aqueous sodium hydrogen carbonate (0.5ml) and saturated aqueous sodium chloride, filtered and concentratedunder reduced pressure to give an oil (20.6 mg). The residual oil waschromatographed on silica gel (400 mg) eluting with a mixture ofmethylene chloride and acetone (10:1 to 2:1) to give4-nitrobenzyl(5R,6S)-3-(2-acetamidoethylsulfinyl)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (15.9 mg) as an oil.

IR (CH₂ Cl₂): 1780, 1740, 1705, 1670, 1605, 1530, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.27 (3H, s), 1.66 (3H, s), 2.02 (2.1H, s), 2.18 (0.9H,s), 2.50-4.05 (7H, m), 4.10-4.70 (1H, m), 5.18 (2H, s), 5.37 (2H, ABq,J=13 Hz), 6.45 (1H, broad s), 7.30-7.80 (2H, m), 8.00-8.45 (2H, m).

EXAMPLE 132 ##STR153##

N,N'-Carbonyldiimidazole (540 mg) was added to a solution of[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl}-4-oxoazetidin-2-yl]aceticacid (1.06 g) in tetrahydrofuran (50 ml) at ambient temperature. Afterstirring for 7 hours at the same temperature, magnesium salt ofmono-p-nitrobenzyl malonate (1.45 g) was added thereto, and theresultant mixture was stirred overnight at ambient temperature. Thesolvent was distilled off in vacuo. The residue was dissolved in ethylacetate (100 ml) and filtered. The filtrate was washed in turn with 0.1Nhydrochloric acid, water, saturated aqueous sodium chloride, aqueoussodium bicarbonate, water, saturated aqueous sodium chloride, 5% aqueouscitric acid, water and saturated aqueous sodium chloride. After dryingover magnesium sulfate, the solution was evaporated. The residue waschromatographed on silica gel (30 g) eluting with a mixture of methylenechloride and ethyl acetate (50:1 to 2:1) to give formy substance, whichwas crystallized from a mixture of chloroform and diisopropyl ether,washed with diisopropyl ether and then dried in vacuo to give4-nitrobenzyl4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(1.31 g), mp 123°-125° C. (dec.).

IR (CH₂ Cl₂): 3400, 1760, 1750, 1720, 1525, 1350 cm⁻¹. NMR (acetone-d₆)δ: 1.64 (3H, s), 1.74 (3H, s), 3.35 (2H, d, J=6.5 Hz), 3.65 (1H, d, J=6Hz), 3.74 (2H, s), 4.20 (1H, m), 5.28 (2H, s), 5.31 (2H, s), 7.18 (1H,s), 7.93 (8H, A₂ B₂, J=8 Hz).

EXAMPLE 133 ##STR154##

A solution of p-toluenesulfonyl azide (435 mg) in acetonitrile (3.9 ml)was added to a solution of 4-nitrobenzyl4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyl-oxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(1.00 g) in acetonitrile (20 ml) at 0° C.

After stirring at 0° C. for 5 minutes, triethylamine (0.923 ml) wasadded dropwise thereto. After stirring at 0° C. for additional 20minutes, the reaction mixture was evaporated. The residue waschromatographed on silica gel (20 g) eluting with a mixture of n-hexaneand ethyl acetate (10:1 to 1:4) to give 4-nitrobenzyl2-diazo-4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(1.08 g).

IR (CH₂ Cl₂): 3400, 2150, 1765, 1750, 1720, 1655, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.68 (3H, s), 1.79 (3H, s), 3.4-3.7 (2H, m), 3.46 (2H, d,J=4.5 Hz), 4.0-4.3 (1H, m) 5.20 (2H, s), 5.35 (2H, s), 6.22 (1H, s),7.80 (4H, A₂ B₂, J=9 Hz), 7.85 (4H, A₂ B₂, J=9 Hz).

EXAMPLE 134 ##STR155##

A mixture of 4-nitrobenzyl2-diazo-4-[(2R,3R)-3-{1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl}-4-oxoazetidin-2-yl]-3-oxobutanoate(1.00 g) and rhodium (II) acetate (5 mg) in benzene (50 ml) was refluxedfor 25 minutes. After cooling to ambient temperature, the mixture wasfiltered through cellulose powder. The filtrate was evaporated to give4-nitrobenzyl(2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate(0.94 g) as an amorphous solid.

IR (CH₂ Cl₂): 1770, 1750, 1525, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.64 (3H, s), 1.84 (3H, s), 2.74 (1H, dd, J=19 Hz, 8 Hz),3.34 (1H, dd, J=19 Hz, 8 Hz), 3.77 (1H, d, J=6 Hz), 4.34 (1H, dt, J=6Hz, 8 Hz), 4.76 (1H, s), 5.18 (2H, s), 5.32 (2H, ABq, J=16 Hz), 7.88(4H, A₂ B₂, J=9 Hz), 7.91 (4H, A₂ B₂, J=9 Hz).

EXAMPLE 135 ##STR156##

To a solution of 4-nitrobenzyl(2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate(58 mg) and 4-(N,N-dimethylamino)pyridine (1.3 mg) in acetonitrile (3ml) was added a solution of diisopropylethylamine (22.4 μl) inacetonitrile (0.21 ml) at 0° C. To the mixture was added a solution ofdiphenyl chlorophosphate (23.3 μl) in acetonitrile (0.21 ml) at 0° C.After stirring at 0° C. for 1.5 hours, the reaction mixture was cooledto -15° C., to which a solution of diisopropylethylamine (74.6 μl) inacetonitrile (0.73 ml) was added. To the mixture was added a solution ofN-(2-mercaptoethyl)acetamide (13.4 mg) in acetonitrile (0.12 ml). Afterstanding overnight at -15° C., the mixture was diluted with ethylacetate (50 ml), washed in turn with water and saturated aqueous sodiumchloride, and dried over magnesium sulfate. After evaporation of thesolvent, the residue was chromatographed on silica gel (2 g) elutingwith a mixture of methylene chloride and acetone (20:1 to 2:1) to give4-nitrobenzyl(5R,6R)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(56 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3400, 1775, 1745, 1695, 1675, 1530, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.68 (3H, s), 1.81 (3H, s), 1.96 (3H, s), 2.8-4.0 (6H,m), 3.76 (1H, d, J=6 Hz), 4.2-4.6 (1H, m), 5.18 (2H, s), 5.38 (2H, ABq,J=15 Hz), 6.30 (1H, broad t, J=6 Hz), 7.88 (4H, A₂ B₂, J=9 Hz), 7.95(4H, A₂ B₂, J=9 Hz).

EXAMPLE 136 ##STR157##

A mixture of 5% palladium on activated carbon (175 mg), dioxane (12.5ml) and 1/30M sodium phosphate buffer (pH 7.0, 5.5 ml) was shaken for anhour under a hydrogen atmosphere (40 psi) at ambient temperature. Asolution of 4-nitrobenzyl(5R,6R)-3-(2-acetamidoethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(175 mg) in a mixture of dioxane (12 ml) and 1/30M sodium phosphatebuffer (pH7.0, 5 ml) was added to the mixture at 0° C. and the resultingmixture was shaken under a hydrogen atmosphere (40 psi) for an hour,during which time the reaction temperature rose to ambient temperature.1% Aqueous solution of sodium bicarbonate (2.29 ml) was added therein at0° C. and the mixture was filtered through cellulose powder. Thefilter-cake was washed with water (3×20 ml). The combined filtrates wereconcentrated to a half volume, washed with ethyl acetate (3×50 ml), andevaporated in vacuo. The residue was dissolved in water (220 ml)containing sodium chloride (6.6 g) and chromatographed on Diaionnon-ionic adsorption resin, HP-20 AG (trade mark, made by MitsubishiChemical Industries) (150-300μ, φ2.2×36 cm) eluting with water (360 ml)and a mixture of water and acetone (10:0 to 7:3, 600 ml). The fractions,whose UV spectra showed λmax 300 nm, were combined and lyophilized togive sodium(5R,6R)-3-(2-acetamidoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(46.5 mg) as white powder.

IR (KBr): 1750, 1650, 1590, 1550, 1400 cm⁻¹.

NMR (D₂ O) δ: 1.29 (3H, s), 1.40 (3H, s), 1.97 (3H, s), 2.90 (2H, t, J=8Hz), 3.04 (1H, dd, J=17 Hz, 10 Hz), 3.36 (2H, t, J=8 Hz), 3.67 (1H, d,J=6 Hz), 3.76 (1H, dd, J=17 Hz, 9 Hz), 4.14 (1H, ddd, J=6 Hz, 9 Hz, 10Hz).

EXAMPLE 137 ##STR158##

To a solution of 4-nitrobenzyl(2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]heptane-2-carboxylate(602 mg) and 4-(N,N-dimethylamino)pyridine (13.6 ml) in acetonitrile (30ml) was added a solution of diisopropylethylamine (0.232 ml) inacetonitrile (2.08 ml) at 0° C. To the mixture was further added asolution of diphenyl chlorophosphate (0.242 ml) in acetonitrile (2.18ml). After stirring at 0° C. for an hour, the mixture was cooled to -15°C. To the mixture was added a solution of diisopropylethylamine (0.775ml) in acetonitrile (6.97 ml) and N-(4-nitrobenzyloxycarbonyl)cysteamine(299 mg) were added. After standing overnight at -15° C., the mixturewas evaporated in vacuo. The residue was dissolved in ethyl acetate (100ml) and the solution was washed in turn with water and saturated aqueoussodium chloride, dried over magnesium sulfate, and evaporated in vacuo.The residue was chromatographed on silica gel (18 g) eluting with amixture of benzene and acetone (20:1 to 6:1) to give 4-nitrobenzyl(5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(716 mg) as an amorphous solid.

IR (CH₂ Cl₂): 3430, 1780, 1745, 1730, 1710, 1605, 1520, 1345 cm⁻¹.

NMR (CDCl₃) δ: 1.64 (3H, s), 1.80 (3H, s), 2.7-3.5 (5H, m), 3.5-4.0 (1H,m), 3.70 (1H, d, J=5 Hz), 4.3 (1H, m), 5.09 (2H, s), 5.13 (2H, s), 5.32(2H, ABq, J=13 Hz), 7.78 (8H, A₂ B₂, J=8 Hz), 7.85 (4H, A₂ B₂, J=8 Hz).

EXAMPLE 138 ##STR159##

To a solution of(3R,4R)-3-(benzyloxycarbonylamino)-4-(2,2-dimethoxyethyl)azetidin-2-one(1.014 g) in tetrahydrofuran (15 ml) were added portionwise a solutionof sodium cyanoborohydride (460 mg) in tetrahydrofuran (2.30 ml) and 2Nhydrochloric acid (7.5 ml) at ambient temperature during a period of 90minutes. The solution was adjusted to pH 7 with saturated aqueous sodiumhydrogen carbonate and concentrated in vacuo. The concentrate wasacidified to pH 4 with 2N hydrochloric acid, saturated with sodiumchloride and extracted four times with chloroform. The combined extractswere dried over magnesium sulfate and evaporated in vacuo. The residuewas chromatographed on silica gel (15 g, eluting with 3-10% methanol indichloromethane) to give a crystalline solid, which was washed withether and collected by filtration to give 553 mg of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 139 ##STR160##

Ozone was bubbled into a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)-azetidin-1-yl]-3-methylbut-2-enoate(119 mg) in ethyl acetate (6 ml) at -78° C. until a permanent blue colordeveloped. The excess ozone was removed by a stream of nitrogen anddimethyl sulfide (0.3 ml) was added. The mixture was allowed to warm to4° C., kept in a refrigerator (4° C.) for 7 hours and left at roomtemperature for 39 hours. The yellow solution was concentrated underreduced pressure and the residue was dissolved in methanol (4 ml).Aqueous potassium hydrogen carbonate (1.0M, 0.4 ml) was added thereinand the resulting mixture was stirred at room temperature for 30minutes. The solution was then cooled to 0° C. and sodium borohydride(22 mg) was added to the solution. After 17 minutes stirring, aceticacid (0.15 ml) was added to the mixture and the mixture was evaporatedin vacuo. The residue was dissolved in chloroform and washed withsaturated aqueous sodium chloride containing sodium hydrogen carbonate.The aqueous layer was extracted twice with chloroform. The combinedextracts were dried over magnesium sulfate and evaporated in vacuo. Theresidue was chromatographed on silica gel (2 g, eluting with 5-10%methanol in dichloromethane) to give 50 mg of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 140 ##STR161##

Ozone was bubbled into a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)-azetidin-1-yl]-3-methylbut-2-enoate(382 mg) in methanol (8 ml) at -78° C. until a permanent blue colordeveloped. After five minutes stirring the excess ozone was removed by astream of nitrogen. Dimethylsulfide (0.4 ml) was added and the solutionwas stirred at -78° C. for 35 minutes. Sodium borohydride (80 mg) wasthen added the solution and the reaction was continued for 40 minutes atthe same temperature and quenched by addition of acetic acid (0.15 ml).The resulting mixture was stirred at -78° C. for 30 minutes, allowed towarm to 0° C. during 50 minutes and concentrated in vacuo. The residuewas dissolved in a 10:1 mixture of ethyl acetate and chloroform (30 ml)and washed in turn with saturated aqueous sodium chloride (twice), amixture of saturated aqueous sodium chloride and saturated aqueoussodium hydrogen carbonate, and saturated aqueous sodium chloride. Theresultant mixture was dried over magnesium sulfate and concentratedunder reduced pressure to give 352 mg of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-2-hydroxyacetate.

IR (CH₂ Cl₂): 3300-3700 (br), 3380, 1770, 1740 (sh) 1720 cm⁻¹.

NMR (CDCl₃) δ: 2.0 (1H, br), 2.97 (2H, brd, J=6 Hz), 3.72 (3H, s), 4.16(1H, dt, J=2,6 Hz), 4.47 (1H, dd, J=2,7 Hz), 5.06 (2H, s), 5.52 (1H,brs), 5.91 (1H, d, J=7 Hz), 7.28 (5H, s), 9.65 (1H, s).

The aldehyde (318 mg) obtained above was dissolved in methanol (5 ml)and the solution was cooled to 0° C. 1N Aqueous potassium hydrogencarbonate (0.5 ml) was added and the mixture was stirred at 0° C. for 5minutes and at ambient temperature for 30 minutes. Sodium borohydride(38 mg) was then added to the mixture at 0° C. and the mixture wasstirred at the same temperature for 15 minutes and quenched by additionof acetic acid (0.15 ml). After concentration in vacuo, the residue wasdissolved in chloroform and washed with brine containing sodium hydrogencarbonate. The aqueous layer was extracted three times with chloroform.The combined extracts were dried over magnesium sulfate and evaporatedin vacuo to give a crystalline solid, which was chromatographed onsilica gel (6 g, eluting with 3-10% methanol in dichloromethane) to give113 mg of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 141 ##STR162##

Ozone was bubbled into a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin-1-yl]-3-methylbut-2-enoate(255 mg) in ethyl acetate (6.5 ml) at -78° C. until a permanent bluecolor developed. The excess ozone was removed by a stream of nitrogen.The solution was allowed to warm to 0° C. and washed with dilute aqueoussodium hydrogen sulfite and brine. The resultant mixture was dried overmagnesium sulfate and concentrated under reduced pressure to give 251 mgof methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(1,2,4-trioxolan-3-yl)-methylazetidin-1-yl]-2-oxoacetate.

IR (CH₂ Cl₂): 3390, 1810, 1745, 1720, 1705 cm⁻¹.

EXAMPLE 142 ##STR163##

To a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(1,2,4-trioxolan-3-yl)-methylazetidin-1-yl]-2-oxoacetate(205 mg) in methanol (4 ml) was added 1N aqueous potassium hydrogencarbonate (0.5 ml) at ambient temperature. The mixture was stirred for25 minutes and cooled to 0° C. Sodium borohydride (40 mg) and 1N aqueouspotassium hydrogen carbonate were added to the mixture at 0° C. Thereaction mixture was stirred at 0° C. for 30 minutes and at ambienttemperature for an additional 30 minutes, and quenched by addition ofacetic acid (0.20 ml). The resulting mixture was concentrated underreduced pressure and the residue was dissolved in chloroform and washedwith brine containing sodium hydrogen carbonate. The aqueous layer wasextracted three times with chloroform. The combined extracts were driedover magnesium sulfate, evaporated in vacuo, and chromatographed onsilica gel (3 g, eluting with 10-30% acetone in dichloromethane) to give66 mg of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 143 ##STR164##

A mixture of platinum oxide (60.0 mg), water (4.2 ml) aqueousdipotassium hydrogen phosphate (1.0M, 0.385 ml) and ethanol (0.6 ml) wasshaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambienttemperature. The mixture was added to a solution of 4-nitrobenzyl(5R,6S)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(60.0 mg) in dioxane (7.2 ml) and shaken for 30 minutes under a hydrogenatmosphere (50 psi) at ambient temperature. The reaction mixture wasfiltered with diatomaceous earth. The filter-cake was washed with water(20 ml) and the combined filtrates (32 ml) were lyophilized over aperiod of 6 hours. The residue was chromatographed on non-ionicadsorption resin, Diaion HP-20-AG (trade mark, made by MitsubishiChemical Industries) (15×260 mm) eluting with water (230 ml) and then amixture of water and methanol (7:3, 140 ml). The fractions showing UVmaxima at 298 nm were collected, concentrated and lyophilized to givepotassium(5R,6S)-3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(12.1 mg) as pale yellow powder.

IR (Nujol): 3350, 1750, 1575, 1380 cm⁻¹.

UV (H₂ O): 298 nm (ε=7970).

NMR (D₂ O) δ: 1.34 (3H, s), 1.38 (3H, s), 3.00-3.38 (6H, m), 3.47 (1H,d, J=3 Hz), 4.22 (1H, dt, J=3.8 Hz).

EXAMPLE 144 ##STR165##

A mixture of platinum oxide (60.0 mg), water (4.2 ml), aqueousdipotassium hydrogen phosphate (1.0M, 0.385 ml) and ethanol (0.6 ml) wasshaken for 30 minutes under a hydrogen atmosphere (50 psi) at ambienttemperature. The mixture was added to a solution of 4-nitrobenzyl(5R,6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-3-[2-(4-nitrobenzyloxycarbonylamino)-ethylthio]-7-oxo-1-azabicyclo-[3.2.0]hept-2-ene-2-carboxylate(60.0 mg) in dioxane (7.2 ml) and shaken for 2 hours under a hydrogenatmosphere (50 psi) at ambient temperature. The reaction mixture wasfiltered using diatomaceous earth and the filter-cake was washed withwater (20 ml). The combined filtrates (32 ml) were lyophilized over aperiod of 4 hours. The residue was chromatographed on non-ionicadsorption resin, Diaion HP-20-AG (trade mark, made by MitsubishiChemical Industries) (13×230 mm) eluting with water (120 ml) and then amixture of water and isopropanol (19:1, 60 ml). The fractions showing UVmaxima at 296 nm were collected, concentrated and lyophilized to givepotassium(5R,6R)-3-(2-aminoethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate(10.4 mg) as pale yellow powder.

IR (Nujol): 3350, 1750, 1580, 1375 cm⁻¹.

UV (H₂ O): 296 nm (ε=6580).

NMR (D₂ O) δ: 1.31 (3H, s), 1.43 (3H, s), 2.70-3.38 (6H, m), 3.69 (1H,d, J=5 Hz), 4.25 (1H, dt, J=5,8 Hz).

EXAMPLE 145 ##STR166##

A solution of osmium tetroxide (0.61 mg) in water (0.05 ml) was added toa solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin-1-yl]-3-methylbut-2-enoate(58 mg) and sodium chlorate (50 mg) in a mixture of tetrahydrofuran (1ml) and water (1 ml) and the mixture was stirred for 17 hours at ambienttemperature. Sodium periodate (60 mg) was then added and stirring wascontinued for 30 minutes. The resulting mixture was diluted with brineand extracted with ethyl acetate. The extract was washed successivelywith brine, brine containing sodium bicarbonate, and brine. The mixturewas dried over magnesium sulfate and concentrated under reduced pressureto give an oil, which was chromatographed on silica gel (1.5 g, elutingwith 2.5% methanol in dichloromethane) to give 49 mg of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate.

IR (CH₂ Cl₂): 3420, 1765, 1725 cm⁻¹.

EXAMPLE 146 ##STR167##

A solution of osmium tetroxide (0.61 mg) in water (0.05 ml) was added toa mixture of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)acetidin-1-yl]-3-methylbut-2-enoate(106 mg) and sodium periodate (36.5 mg) in a mixture of tetrahydrofuran(1 ml) and water (1 ml). After 25 minutes stirring at ambienttemperature, additional sodium periodate (101.2 mg) was added and themixture was stirred at ambient temperature for 4.5 hours. The resultingmixture was diluted with brine containing sodium bicarbonate andextracted twice with dichloromethane. The combined extracts were driedover magnesium sulfate and evaporated to give 110 mg of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoateas an oil.

IR (CH₂ Cl₂): 3420, 1765, 1725 cm⁻¹.

EXAMPLE 147 ##STR168##

Sodium borohydride (10 mg) was added to a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(2-oxoethyl)azetidin-1-yl]-3-methylbut-2-enoate(49 mg) in methanol (1 ml) at 0° C. The mixture was stirred at the sametemperature for 20 minutes and quenched with acetic acid (˜0.05 ml). Theresulting solution was evaporated in vacuo. The residue was dissolved indichloromethane and washed with brine containing sodium bicarbonate. Theextract was dried over magnesium sulfate, evaporated, andchromatographed on silica gel (1.5 g, eluting with 5-10% acetone indichloromethane) to give 39 mg of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate.

IR (CH₂ Cl₂): 1765, 1720 (br) cm⁻¹.

NMR (CDCl₃): 1.7-2.2 (2H, m), 1.90 (3H, s), 2.17 (3H, s), 3.4-4.0 (4H,m), 3.71 (3H, s), 4.56 (1H, dd, J=2,7 Hz), 5.11 (2H, s), 6.10 (1H, m),7.33 (5H, s).

EXAMPLE 148 ##STR169##

A stream of ozone was bubbled into a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)-2-oxoazetidin-1-yl]-3-methylbut-2-enoate(76 mg) in methanol (6 ml) at -78° C. until the starting materialdisappeared. The excess ozone was removed by a stream of nitrogen.Dimethyl sulfide (0.3 ml) was added and the resulting solution wasallowed to warm to ambient temperature for five hours. The solution wascooled to 0° C., to which a solution of sodium methoxide in methanol(0.1M, 0.25 ml) was added. The mixture was stirred at 0° C. for 30minutes and quenched by addition of acetic acid (excess). The solutionwas evaporated in vacuo and the residue was chromatographed on silicagel (1.5 g, eluting with 2.5-10% methanol in dichloromethane) to give 46mg of a crystalline solid, which was triturated in diethyl ether andfiltered to give 40 mg of(3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 149 ##STR170##

A stream of ozone was bubbled into a solution of methyl2-[(3R,4R)-3-benzyloxycarbonylamino-2-oxo-4-(prop-2-enyl)azetidin-1-yl]-3-methylbut-2-enoate(85.6 g) in methanol (1.54 l) at -78° C. until a permanent blue colordeveloped. After 30 minutes the excess ozone was removed by purgingnitrogen into the solution and dimethyl sulfide (85.6 ml) was thenadded. The solution was allowed to warm to 4° C., kept at the sametemperature for 15 hours and left at ambient temperature for 24 hours.To the resulting solution were added methyl orthoformate (171.2 ml) andp-toluenesulfonic acid monohydrate (1.18 g). The solution was heated at50° C. for three hours, cooled to ambient temperature, neutralized withpyridine (0.71 ml) and concentrated in vacuo. The residue was dissolvedin ethyl acetate (1.5 l) and washed with brine containing 1Nhydrochloric acid, and brine. The aqueous layers were combined andextracted with ethyl acetate. The combined organic layers were washedwith brine, brine containing sodium bicarbonate, and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was dissolved inmethanol (1.54 l) and cooled to 4° C. A 4.9M methanolic sodium methoxide(0.151 ml) was then added and the resultant solution was stirred for 15minutes, quenched with acetic acid (0.151 ml) and concentrated underreduced pressure. The residue was dissolved in ethyl acetate, washed inturn with brine containing sodium bicarbonate and brine, dried overmagnesium sulfate, and evaporated in vacuo. The residue was subjected tocolumn chromatography on silica gel (1 kg, eluting with 10 to 30%acetone in dichloromethane). The eluate was concentrated under reducedpressure to give a residue, which was crystallized from a 1:1 mixture ofdiethyl ether and diisopropyl ether to give 48.23 g of(3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one.

IR (CH₂ Cl₂): 1770, 1720 cm⁻¹.

EXAMPLE 150 ##STR171##

A solution of(6R,7RS)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-7-isocyano-1-aza-3-oxabicyclo[4.2.0]-octan-8-one(920 mg), triphenyltin hydride (1.694 g) and azobisisobutyronitrile(63.4 mg) in benzene (46 ml) was heated at 50° C. for thirty minutesunder a nitrogen atmosphere. The mixture was cooled to ambienttemperature. The precipitates were filtered off and washed with benzene.The filtrate and washings were combined and chromatographed on silicagel (27.6 g, eluting with 10 to 25% acetone in dichloromethane) to givea crude product mixture, which was re-chromatographed on silica gel (46g; 230-400 mesh, eluting with a 6:1 to 1:2 mixture of hexane and ethylacetate) to give 513 mg of(6R,7R)-2,2-dimethyl-7-(1-hydroxy-1-methylethyl)-1-aza-3-oxabicyclo[4.2.0]octan-8-oneafter crystallization from diisopropyl ether and 170 mg of its 7S isomeras a crystalline solid.

EXAMPLE 151 ##STR172##

Ozone was bubbled into a solution of methyl3-methyl-2-{(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(prop-2-enyl)azetidin-1-yl}but-2-enoate(100 mg) in a mixture of methanol (3 ml) and ethyl acetate (3 ml) at-70° C. until a blue color appeared. After stirring for 20 minutes at-70° C., the excess ozone was removed by a stream of nitrogen at thesame temperature and dimethyl sulfide (1 ml) was added to the mixture,which was allowed to warm to ambient temperature over a period of anhour and to stand at 20° C. for 20 hours. After evaporation of thesolvent, the residue was dissolved in methanol (5 ml). Trimethylorthoformate (0.5 ml), dimethyl sulfide (0.3 ml) and p-toluenesulfonicacid monohydrate (4.1 mg) were added to the solution and the mixture washeated at 50° C. for 50 minutes. After cooling, pyridine (3 drops) wasadded to the mixture. The resulting solution was evaporated in vacuo,dissolved in ethyl acetate (20 ml) and washed in turn with water, 0.1Nhydrochloric acid, water, aqueous sodium bicarbonate and brine. Theethyl acetate layer was dried over magnesium sulfate and evaporated invacuo. The residue was dissolved in methanol (5 ml) and the solution washeated at 50° C. for 5 hours. After evaporation of the solvent, theresidue was chromatographed on silica gel (2 g) eluting with a mixtureof methylene chloride and ethyl acetate (20:1 to 1:2) to give(3R,4R)-4-(2,2-dimethoxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one(75 mg) as an oil.

IR (CH₂ Cl₂): 3400, 1760, 1520, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.70 (3H, s), 1.78 (3H, s), 2.0-2.5 (2H, m), 3.42 (6H,s), 3.67 (1H, d, J=5 Hz), 3.8-4.1 (1H, m), 4.55 (1H, t, J=5.5 Hz), 5.31(2H, s), 6.56 (1H, s), 7.68 (2H, d, J=9 Hz), 8.38 (2H, d, J=9 Hz).

EXAMPLE 152 ##STR173##

A solution of(3R,4R)-4-(2,2-dimethoxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one(64 mg) in 80% aqueous acetic acid (3.0 ml) was heated at 50°-55° C. for4 hours. After evaporation of the solvent, the residue was dissolved inethyl acetate (20 ml) and the solution was washed with aqueous sodiumbicarbonate. The aqueous layer was extracted with ethyl acetate (10 ml).The organic layers were combined, washed with water and brine, driedover magnesium sulfate and evaporated in vacuo to give(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-(2-oxoethyl)-azetidin-2-one(55 mg) as a solid.

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 153 ##STR174##

A solution of(3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-azetidin-2-one(50 mg) in acetone (3 ml) was added to a solution of 2N Jones reagent(0.284 ml) in acetone (3 ml) at ambient temperature over a period of 30minutes and the mixture was stirred for 30 minutes. After addition of anexcess of isopropyl alcohol to the mixture, the solvent was evaporatedoff. The residue was dissolved in chloroform and washed with water. Theaqueous layer was extracted twice with chloroform. The organic layerswere combined, washed with brine, dried over magnesium sulfate andevaporated in vacuo. The residue was dissolved in chloroform (5 ml) andthe solution was extracted with 0.1N aqueous solution of sodiumbicarbonate (2 ml), 0.05N aqueous solution of sodium bicarbonate (2 ml)and water. The aqueous extracts were combined, acidified with 1Nhydrochloric acid and extracted three times with chloroform. Thecombined chloroform extracts were washed with brine, dried overmagnesium sulfate and evaporated to give{(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-4-oxoazetidin-2-yl}aceticacid (56 mg).

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 154 ##STR175##

To a solution of methyl2-{(3R,4R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-4-(prop-2-enyl)azetidin-1-yl}-3-methylbut-2-enoate(50 mg) in acetone (2.79 ml) were added water (0.93 ml) and a 0.7Msolution of phosphate buffer (pH 6.8, 1.86 ml) at ambient temperature.Sodium periodate (139 mg) was added to the resulting suspension atambient temperature and the mixture was stirred for 20 minutes.Potassium permanganate (26 mg) was then added and the resulting mixturewas stirred for 26 hours at ambient temperature. The mixture wasacidified with 2N hydrochloric acid (2 ml) and filtered usingdiatomaceous earth, and the filter-cake was washed with acetone andwater. The filtrates were combined and concentrated under reducedpressure to a half volume. The concentrate was extracted three timeswith chloroform. The organic layers were combined, washed with brine andextracted with 5% aqueous sodium bicarbonate and water. The combinedaqueous extracts were acidified with 2N hydrochloric acid and extractedthree times with chloroform. The organic extracts were combined, washedwith brine, dried over magnesium sulfate and evaporated in vacuo to give{(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidin-2-yl}aceticacid (16 mg).

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 155 ##STR176##

Pyridinium dichromate (3.74 g) was added to a solution of(3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-oxo-azetidine(1.00 g) in N,N-dimethylformamide (20 ml) at 0° C., and the stirringmixture was allowed to warm to ambient temperature. After stirring atambient temperature for 16 hours, the reaction mixture was poured into amixture of ethyl acetate (150 ml), 10% aqueous sodium bisulfite (40 ml)and 3N hydrochloric acid (15 ml). The organic layer was separated andthe remaining aqueous layer was extracted with ethyl acetate (100 ml×2).The organic layers were combined, washed in turn with water and anaqueous sodium chloride, dried over magnesium sulfate, and evaporated invacuo.

The residue was dissolved in chloroform (30 ml) and the resultantsolution was extracted with 5% aqueous sodium bicarbonate (20 ml), 2.5%aqueous sodium bicarbonate (20 ml) and then water (15 ml×2). The aqueoussolutions were combined and acidified with 3N hydrochloric acid,followed by re-extraction three times with chloroform (20 ml). Thecombined extracts were washed with an aqueous sodium chloride, driedover magnesium sulfate, and evaporated to give{(2R,3R)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxo-azetidin-2-yl}aceticacid (810 mg).

IR (CH₂ Cl₂): 1735, 1520, 1350 cm⁻¹.

EXAMPLE 156 ##STR177##

A solution of diisopropylethylamine (0.386 ml) in acetonitrile (0.34 ml)was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0] heptane-2-carboxylate (100 mg) and 4-(N,N-dimethylamino)-pyridine (2.3 mg) in acetonitrile (5 ml) at 0° C.

A solution of diphenyl chlorophosphate (0.0402 ml) in acetonitrile (0.36ml) was then added at 0° C.

After stirring at 0° C. for 30 minutes, the mixture was evaporated invacuo and the residue was dissolved in ethyl acetate. The organicsolution was washed in turn with water and brine, dried over magnesiumsulfate, and evaporated to give 4-nitrobenzyl(5R,6R)-3-(diphenoxyphosphoryloxy)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (148 mg).

IR (CH₂ Cl₂): 1780, 1745, 1725, 1640, 1520, 1485, 1345 cm⁻¹.

NMR (CDCl₃): 1.61(s, 3H), 1.80(s, 3H), 3.14(dd, 1H, J=9.16 Hz), 3.73(d,1H, J=6 Hz) 3.5-4.0(m, 1H), 4.0-4.3(m, 1H), 5.00 (s, 2H), 5.18(ABq, 2H,J=14 Hz), 7.0-7.7(m, 14H), 7.8-8.2(m, 4H).

EXAMPLE 157 ##STR178##

A solution of diisopropylethylamine (0.0579 ml) in acetonitrile (0.5 ml)was added to a solution of 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0] heptane-2-carboxylate (150 mg) and 4-(N,N-dimethylamino)pyridine (3.38 mg) in acetonitrile (20 ml) at 0° C. Asolution of diphenylchlorophosphate (78 mg) in acetonitrile (0.54 ml)was added to the mixture, which was stirred at 0° C. for 15 minutes.Sodium iodide (415 mg) and silver (Z)-2-acetamidoethylenethiolate (93mg) were added at 0° C. and the mixture was stirred at 0° C. for 2.5hours.

After the precipitate was filtered off, the filtrate was evaporated invacuo and the residue was dissolved in ethylacetate (50 ml). The organicsolution was washed in turn with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was chromatographed onsilica gel (4 g) eluting with a mixture of benzene and acetone(20:I-8:1) to give 4-nitrobenzyl(5R,6R)-3-[(Z)-2-acetamidovinyl-thio]-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (155 mg) as an oil.

IR (CH₂ Cl₂): 1785, 1750, 1710, 1630, 1515, 1350 cm⁻¹.

NMR (CDCl₃) δ: 1.62(s, 3H), 1.78(s, 3H), 2.06(s, 3H), 2.96(dd, 1H, J=11,18 Hz), 3.66 (dd, 1H, J=8, 18 Hz), 3.76(d, 1H, J=5 Hz), 4.0-4.5(m, 1H),5.14(s, 2H), 5.28(d, 1H, J=7 Hz), 5.37(ABq 2H, J=13 Hz), 7.3-7.8(m, 6H),8.22 (d, 4H, J=8 Hz).

EXAMPLE 158 ##STR179##

A mixture of 4-nitrobenzyl(5R,6R)-3-[(Z)-2-acetamidovinylthio]-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylate(100 mg), platinum (IV) oxide monohydrate (50 mg), ethanol (1 ml) and0.1 M aqueous solution of dipotassium hydrogen phosphate (4.68 ml) in amixture of water (5 ml) and dioxane (12 ml) was shaken under a hydrogenatmosphere (40 psi) at ambient temperature for an hour. After thecatalyst was filtered off, the filtrate was evaporated to the halfvolumn.

The aqueous solution was washed three times with ether and evaporated.The residue was dissolved in water (50 ml) and potassium chloride (2.5g) was added. The aqueous solution was chromatographed on a column ofnon-ionic adsorption resin Diaion HP-20 AG (trade mark, MitsubishiChemical Industries) eluting with water (200 ml) and 10% aqueousisopropyl alcohol (200 ml). The fractions, whose UV spectra showed λ max308 nm, were combined and lyophilized to give potassium(5R,6R)-3-[(Z)-2-acetamido-vinylthio]-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0] hept -2-ene-2-carboxylate (30 mg) as powder.

IR (nujol): 1750, 1670 1620, 1585 cm⁻¹.

UV (H₂ O): λmax 234 nm (ε=11460), 308 nm (11650).

What we claim is:
 1. A carbapenam compound of the formula: ##STR180##wherein R_(h) ¹ is 1-hydroxy-1-methylethyl or 1-hydroxy-1-methylethylprotected by a removable hydroxy protecting group and R⁸ is carboxy orcarboxy protected by a removable carboxy protecting group and apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, in which R_(h) ¹ is 1-hydroxy-1-methylethyl protected by aremovable hydroxy protecting group and R⁸ is carboxy protected by aremovable carboxy protecting group.
 3. A compound according to claim 2,in whichR_(h) ¹ is 1-[mono(or di ortri)phenyl(lower)alkoxycarbonyl]-1-methylethyl optionally substituted bynitro and R⁸ is mono(or di or tri)phenyl(lower)alkoxycarbonyl optionallysubstituted by nitro.
 4. A compound according to claim 3, in whichR_(h)¹ is 1-(4-nitrobenzyloxycarbonyloxy)-1-methylethyl and R⁸ is4-nitrobenzyloxycarbonyl.